2018 Bordeaux thth SEPTEMBER Symposium 56 ed.ed. 24-25-26 on IECB Auditorium Foldamers
Plenary Speakers
Jonathan Clayden (Univ. Bristol, UK)
David Liu (Harvard Univ., USA)
Scott Miller (Yale Univ., USA)
Jonathan Nitschke (Univ. Cambridge, UK)
Hanadi Sleiman (McGill Univ., USA)
thth ed. 56 ed. Program & Abstract Book http://www.iecb.u-bordeaux.fr/foldamers2018 @foldamers_Bdx 6th Symposium on Foldamers 2018 Organizing Committee
Co-Chairmen Gilles Guichard (IECB & CBMN, CNRS, Univ. Bordeaux, France) & Ivan Huc (Ludwig-Maximilians-Universität München, Germany)
Organizing Committee Christel Dolain, Yann Ferrand, Gilles Guichard, Ivan Huc, Victor Maurizot IECB & CBMN, CNRS, Univ. Bordeaux Ludwig-Maximilians-Universität München, Germany
Sponsors and Partners The 6th Symposium on Foldamers 2018 is organized and financially supported by the following institutions and companies:
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Symposium on Foldamers Bordeaux 2018 Welcome to the 6th Symposium on Foldamers 2018
Dear participants,
Welcome to Bordeaux, France and to the 2018 Foldamer Symposium !
This is the sixth edition of a series of symposia which took place in Bordeaux in 2010, 2012, 2015, 2016 and in Paris in 2013. This series of conferences dedicated to Foldamer science was initiated in the frame of a COST (European Cooperation in Science and Technology) action dedicated to the advancement of foldamers back in 2009.
We are grateful to our sponsors and exhibitors for their generous support and for making this conference possible.
The 2018 edition of the foldamer symposium was sold out, with 125 registered participants (maximum capacity of the IECB conference room). We are committed to making this meeting fully international and this edition is no exception to the rule with participants coming from 15 countries across America, Asia, and Europe and more than 90% of our speakers coming from foreign universities.
We are happy to welcome many new participants this year with almost 80% of the speakers presenting for the first time at the Bordeaux Symposium. This ability to renew speakers and topics from biotic to abiotic systems reflects the attractiveness and liveliness of a truly interdisciplinary field.
We hope you all enjoy the symposium, and Indian summer in Bordeaux.
The organizing committee.
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Symposium on Foldamers Bordeaux 2018 Local Transport Information
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Symposium on Foldamers Bordeaux 2018 Conference Program Overview
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Symposium on Foldamers Bordeaux 2018 Symposium Program
Monday, September 24 Mo 12:30–13:45 Arrival/registration
13:45–14:00 Welcome address
Session Chair: Galia Maayan 14:00–14:50 PL1 Jonathan Clayden (University of Bristol, UK) “Dynamic foldamers: structures and strategies for responsive molecular systems”
14:50-15:10 SL1 Peter Knipe (Queen’s University, UK) “Exploring 3D Space Monomer-by-Monomer”
15:10-15:30 SL2 Francesco De Riccardis (University di Salerno, Italy) “Central-to-Conformational Chirality Transfer in Cyclic Peptoids”
15:30-16:00 KL1 Claudia Höbartner (Julius-Maximilians-Universität Würzburg, Germany) “DNA catalysts and RNA aptamers: functional nucleic acids by in vitro selection and
rational engineering”
16:00–16:30 Coffee Break
Session Chair: Tomohisa Sawada 16:30-16:50 SL3 Valentina Corvaglia (Ludwig-Maximilians-Universität München, Germany) “The shape determines the function: aromatic foldamers that mimic surface features of B-DNA”
16:50-17:10 SL4 Bradley Pentelute (Massachusetts Institute of Technology, USA) “Synthetic polymer xenoproteins”
17:10-17:30 SL5 Sébastien Goudreau (UREkA, France) “Peptide-oligourea hybrid foldamers and ureidopeptides as new modalities in drug discovery”
17:30–17:50 SL6 Aurelio Mateo-Alonso (University of the Basque Country, Spain) “Piling Up Polycyclic Aromatic Hydrocarbons: Stacks, Foldamers and Supramolecular Polymers with Enhanced Conductances”
17:50–18:20 KL2 Akif Tezcan (University of California San Diego, USA) “Chemical Design of Functional Protein Assemblies”
19:00– Welcome Reception at IECB y, September 24
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Symposium on Foldamers Bordeaux 2018 Tuesday, September 25
Session Chair: Christian Schafmeister 9:30–10:20 PL2 David Liu (Harvard University, USA) “Evolution of Sequence-Defined Highly Functionalized Nucleic Acid Polymers” 10:20–10:50 KL3 Samuel Gellman (University of Wisconsin-Madison, USA) “Bifunctional Foldamer Catalysis”
10:50–11:20 Coffee Break
Session Chair: Peter Knipe 11:20–11:40 SL7 Vojislava Pophristic (University of the Sciences, USA) “Computer Led Design of Functional Arylamide Foldamers”
11:40–12:00 SL8 Christian Schafmeister (Temple University, USA) “Developing applications for Molecular Lego with in silico Evolution”
12:00-12:20 SL9 Tushar Chakraborty (Indian Institute of Science, India) “Studies on Glycosylated Sugar Amino Acid Foldamers”
12:20-12:50 KL4 Harry Anderson (Oxford University, UK) “Expressions of Cooperativity in the Synthesis and Properties of Porphyrin Nanorings”
12:50–14:30 Buffet lunch at premises and Poster Session
Session Chair: Tushar Chakraborty 14:30–15:00 KL5 Marcey Waters (University of North Carolina, USA) “Communication through Noncovalent Networks” 15:00–15:20 SL10 Tomohisa Sawada (The University of Tokyo, Japan) “Higher-order peptide nanostructures via metal-induced folding and assembly” 15:20–15:40 SL11 Masahiko Yamaguchi (Tohoku University, Japan) “Chiral Symmetry Breaking Exhibited by Racemic Helicene Oligomers” 15:40–16:00 SL12 James Petersson ( University of Pennsylvania, USA) “Thioamide modifications of the peptide backbone”
16:00–16:30 Coffee Break
Session Chair: Anne-Sophie Duwez 16:30–16:50 SL13 Zigang Li (Peking University, China) “Stabilized Peptides to Target PPIs” 16:50–17:10 SL14 Aya Tanatani (Ochanomizu University, Japan) “Helical Foldamers Based on the Conformational Properties of Aromatic Amides” 17:10–17:30 SL15 Tamas Martinek (University of Szeged, Hungary) “Rationally designed antimicrobial foldamers against antibiotic resistance” 17:30–18:20 PL3 Hanadi Sleiman (McGill University, Canada) “DNA Nanostructures for Cellular Delivery of Therapeutics”
20:00- Gala Dinner at Hotel Mercure Bordeaux Cité Mondiale
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Symposium on Foldamers Bordeaux 2018 Wednesday, September 26
Session Chair: Aurelio Mateo-Alonso 9:30–10:20 PL4 Scott Miller (Yale University, USA) “Searching for Selective Reactions in Complex Molecular Environments with Peptide-Based Catalysts” 10:20–10:50 KL6 Christian Olsen (University of Copenhagen, Danemark) “Functionalizing helical -peptoids”
10:50–11:20 Coffee Break
Session Chair: Tamas Martinek 11:20-11:40 SL16 Galia Maayan (Technion – Israel Institute of Technology, Israel) “Recent advances in metallopeptoids: electrocatalytic water oxidation and the first examples of metallopeptoid helicates” 11:40–12:00 SL17 Joseph Meisel (New York University, USA) “MAMBA: A Laterally-Flexible and Functionally Diverse Oligoamide Foldamer” 12:00–12:20 SL18 Tomohiko Ohwada (The University of Tokyo, Japan) “Acceleration and sense selectivity of amide rotation by side-chain stapling of bicyclic β-proline dimers” 12:20–12:50 KL7 Nicolas Giuseppone (Université de Strasbourg, France) “Out-of-equilibrium Integration of Molecular Machines“
12:50–14:30 Buffet lunch at premises and Poster Session
Session Chair: James Petersson 14:30–15:00 KL8 Christian Heinis (Ecole Polytechnique Fédérale de Lausanne, Switzerland) “Phage display selection of chemically cyclized peptides for the development of therapeutics” 15:00–15:20 SL19 Zeyuan Dong (Jilin University, China) “Helical Polymer Channels” 15:20–15:40 SL20 Anne-Sophie Duwez (University of Liège, Belgium) “Single-molecule force spectroscopy of synthetic foldamers” 15:40–16:00 SL21 Chris Serpell (University of Kent, UK) “Self-assembling and functional polyphosphoesters beyond nucleic acids”
16:00–16:30 Coffee Break
Session Chair: Vojislava Pophristic 16:30–17:00 KL9 Scott Hartley (Miami University, USA) “Controlling the Folding and Covalent Assembly of ortho-Phenylenes” 17:00–17:50 PL5 Jonathan Nitschke (University of Cambridge, UK) “Helicates and Their Three-dimensional Analogs”
17:50–18:10 Closing address
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Symposium on Foldamers Bordeaux 2018
Oral Presentation Abstracts
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Symposium on Foldamers Bordeaux 2018 Plenary Lecture PL1
Dynamic foldamers: structures and strategies for responsive molecular systems
Jonathan Clayden
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS [email protected]
Foldamers, by definition, have a well defined conformation. Yet it is becoming clear that many of the biomolecules (peptides and proteins in particular) that they aim to mimic do not always share this feature of conformational uniformity. Indeed, for molecules involved in biological signalling, conformational changes are central to their function. We have been exploring the possibilities offered by loosening the definition of a foldamer to include switchable structures that have more than one accessible conformation.[1,2] This lecture will describe the design and utility of such dynamic foldamers[3] in the development of responsive systems that can use conformational change as a means of processing and communicating information. It will discuss the structural limitations of symmetry imposed by an ideally switchable structure, and show how conformational uniformity may be quantified.[4,5] It will outline the application of alternative switching mechanisms in the design of extended molecules that respond selectively to chemical signals in solution and in the membrane phase.[6,7]
Figure 1. Designs for dynamic foldamers. (a) The acidic thiourea function induces a directional preference in the entire chain of directionally switchable ureas. (a) A chiral carboxylate ligand (red), bound by a Cu(II) 'cofactor', induces a screw sense preference, detectable by a remote fluorescent reporter (blue), in an otherwise achiral helical chain.
References [1] M. De Poli, W. Zawodny, O. Quinonero, M. Lorch, S. J. Webb, J. Clayden, Science 2016, 352, 575–580. [2] F. G. A. Lister, B. A. F. Le Bailly, S. J. Webb, J. Clayden, Nature Chem. 2017, 9, 420–425. [3] B. A. F. Le Bailly, J. Clayden, Chem. Commun. 2016, 52, 4852–4863. [4] M. Tomsett, I. Maffucci, B. A. F. Le Bailly, L. Byrne, S. M. Bijvoets, M. G. Lizio, J. Raftery, C. P. Butts, S. J. Webb, A. Contini, et al., Chem. Sci. 2017, 8, 3007–3018. [5] B. A. F. Le Bailly, L. Byrne, V. Diemer, M. Foroozandeh, G. A. Morris, J. Clayden, Chem. Sci. 2015, 6, 2313– 2322. [6] J. Brioche, S. J. Pike, S. Tshepelevitsh, I. Leito, G. A. Morris, S. J. Webb, J. Clayden, J. Am. Chem. Soc. 2015, 137, 6680–6691. [7] R. Wechsel, M. Žabka, J. W. Ward, J. Clayden, J. Am. Chem. Soc. 2018, 140, 3528–3531.
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Symposium on Foldamers Bordeaux 2018 Keynote Lecture SL1
Exploring 3D Space Monomer-by-Monomer
Peter C. Knipe,a Zachariah Lockharta
aSchool of Chemistry and Chemical Engineering, Queen’s University, Belfast; www.knipechem.co.uk [email protected]
Structural mimicry of biopolymers and the development of new functional macromolecules requires exquisite control over conformation. One method to achieve this in foldamers is to exploit local interactions between monomers to govern the local conformation, and use their overall sequence to control the global conformation.[1] Here, we will highlight our results exploring the use of dipolar repulsion between alternating imidazolidin-2-ones and nitrogen-containing aromatic heterocycles as a local conformation-controlling force (Figure 1, red arrows).[2]
Figure 1. Construction of foldamers from monomers that control conformation at a local level – analogous to building a Scalextric® race track.
This approach allows the formation of both helical and extended foldamers, as well as mixed hetereo- oligomers that exhibit multiple secondary structural domains within the same molecule. Recent results using the same approach to the synthesis of macrocycles will also be outlined.
References [1] M. Barboiu, A. M. Stadler, J. M. Lehn, Angew. Chem. Int. Ed. 2016, 55, 4130–4154. [2] Z. Lockhart, P. C. Knipe, Angew. Chem. Int. Ed. 2018, asap, doi:10.1002/anie.201802822
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL2
Central-to-Conformational Chirality Transfer in Cyclic Peptoids
Assunta D’Amato, Rosaria Schettini, Giovanni Pierri, Consiglia Tedesco, Chiara Costabile, Irene Izzo, Francesco De Riccardis
aDepartment of Chemistry and Biology, University di Salerno, Fisciano (SA), 84084, Italy [email protected]
The field of peptoids (N-substituted glycines oligomers) is one of the most promising in the peptidomimetic arena. However, although hundreds of structures have been reported in recent times,[1] few reports deal with the stereochemistry of their oligoamide framework and the presence of conformational enantiomers or diastereoisomers.[2] In this communication we demonstrate (with X-Ray diffraction analysis, circular dichroism, and NMR spectroscopy) the pervasiveness of conformational chirality in conformationally stable (on the NMR time scale) cyclic peptoids and propose a simple method to define their geometric arrangement in terms of planar chirality (using the Rp/Sp descriptors based on the classic Cahn, Ingold and Prelog priority rules).[3] We will also report the first stereoselective syntheses of conformationally chiral cyclic peptoids, exploiting central-to-conformational chirality transfer. [2b]
Bn O Bn O Bn O Bn O (R) (S) N OH N OH HN N HN N HN N N OH O H O (S) O H CH3 O H3C O O a O a a
Bn O Bn O O N O O N O O O O O N + N O O O CH3 H O Bn N N N N H Bn CH3 H3C N N H3C N N (S) (S) H (R) (S) H opposite conformational chirality of peptoid rings opposite conformational chirality of peptoid rings Figure 1. Central-to-conformational chirality induction in trimeric cyclic peptoids.
The precise analysis of the stereochemical features of shape-persistent oligomeric macrolactams and the establishment of unambiguous way to define their conformational properties are necessary steps for rational design of peptoid foldamers and their appropriate use in asymmetric organocatalysis, chiral recognition, supramolecular chemistry, and crystal engineering.
References [1] a) A. M. Webster, S. L. Cobb, Chem. Eur. J., 2018, 14, in press.. b) A. S. Culf, R. J. Oulette, Molecules, 2010, 15, 5282. [2] a) A. D’Amato, R. Volpe, M. C. Vaccaro, S. Terracciano, I. Bruno, M. Tosolini, C. Tedesco, G. Pierri, P. Tecilla, C. Costabile, G. Della Sala, I. Izzo, F. De Riccardis, J. Org. Chem., 2017, 82, 8848. b) A. D’Amato, G. Pierri, C. Costabile, G. Della Sala, C. Tedesco, I. Izzo, F. De Riccardis, Org. Lett., 2018, 20, 640. c) A. D’Amato, R. Schettini, G. Della Sala, C. Costabile, C. Tedesco, I. Izzo, F. De Riccardis, Org. Biomol. Chem., 2017, 15, 9932. [3] a) R. S. Cahn, C. Ingold, V.Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385. b) V. Prelog, G. Helmchen, Angew. Chem., Int. Ed. Engl., 1982, 21, 567. c) B. Testa, Helv. Chim. Acta, 2013, 96, 351.
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Symposium on Foldamers Bordeaux 2018 Keynote Lecture KL1
DNA catalysts and RNA aptamers: functional nucleic acids by in vitro selection and rational engineering
Claudia Höbartner
Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany [email protected]
Natural and artificial functional nucleic acids fold into complex three-dimensional structures that form the basis for their sophisticated functions to recognize specific ligands and catalyze chemical reactions. In the laboratory, new catalytic activities for DNA and RNA can be evolved by iterative selection and amplification of desired sequences from an initially random library. Numerous reactions can now be catalyzed by DNA, but details of the catalytic mechanisms are still largely unknown, and until recently no structural information on any DNA enzyme was available. Aiming at a deeper understanding of nucleic acid catalysis and enhancing the abilities of DNA enzymes for various applications, we focus on RNA-ligating DNA enzymes for the synthesis of site- specifically labeled RNA, and on RNA-cleaving DNA enzymes for the analysis of natural RNA modifications. Using combinatorial characterization methods, we identified essential nucleotides and truncated the catalytic core of the DNA enzymes. The minimized DNA was successfully crystallized, which resulted in the first structure of a catalytic DNA.[1] The structure revealed fascinating insights into a complex active site made from DNA, and provided clues on the regioselectivity of bond formation and substrate preferences for the DNA-catalyzed reaction. Structure-guided mutagenesis allowed engineering of the catalyst for efficient ligation of previously inert RNA substrates. The second class of functional nucleic acids under investigation are fluorogen-activating RNA aptamers (FLAPs) that have emerged as powerful tools for tagging and visualizing RNA in vitro and in vivo. The RNA specifically binds a small molecule ligand that is non-fluorescent when free in solution but exhibits enhanced fluorescence emission in the bound state. Rational engineering of the active site is challenging in the absence of a crystal structure, but in combination with strategic functionalization of the ligand, we report an RNA aptamer that induces highly red-shifted fluorescence emission with a large Stokes shift.[2]
Figure 1. Three-dimensional structure of an RNA-ligating DNA catalyst in complex with the ligation product (red dot represents the ligation site, the RNA is in blue, the DNA binding arms in grey, and the core nucleotides in red and black).
References [1] A. Ponce-Salvatierra, K. Wawrzyniak-Turek, U. Steuerwald, C. Höbartner, V. Pena, Nature 2016, 529, 231-34. [2] C. Steinmetzger, N. Palanisamy, K.R. Gore, C. Höbartner, 2018, submitted.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL3
The shape determines the function: aromatic foldamers that mimic surface features of B-DNA
Krzysztof Ziach ,a Céline Chollet,a Vincent Parissi,b Panchami Prabhakaran ,a Mathieu Marchivie ,c Valentina Corvaglia ,a,d Partha Pratim Bose ,a Katta Laxmi-Reddy,a Frédéric Godde,a Jean-Marie Schmitter,a Stéphane Chaignepain,a Philippe Pourquier ,e Ivan Huc a,d
aUniv. Bordeaux – CNRS – IPB, CBMN Laboratory (UMR5248), Institut Européen de Chimie et Biologie, Pessac, France, bUniv. Bordeaux – CNRS, Laboratoire de Microbiologie Fondamentale et Pathogénicité (UMR5234), Bordeaux, France, cUniv. Bordeaux – CNRS, ICMCB (UPR9048), Pessac, France, dDepartment für Pharmazie Ludwig-Maximilians-Universität, München, Germany, eINSERM U1194, Institut de Recherche en Cancérologie de Montpellier & Université de Montpellier, Montpellier, France. [email protected]
Nucleic acids are essential biomolecules that encode all the genetic information necessary for life. Structurally, the main feature is their ability to hybridize through base-pairing to form stable double- strand helix structure that is involved in innumerable interactions with proteins thanks to the array of phosphate ions and chemical groups belonging to the nucleobases that are exposed in the grooves[1,2]. Although naturally occurring DNA-mimic proteins[3,4] and numerous artificial DNA mimics[5,6] have been described, synthetic molecular architectures, designed to reproduce the spatial distribution of charges at the surface of double-stranded DNA, were until now not known. Herein, we report the design, synthesis and structural characterization of single helix aromatic oligoamides that efficiently reproduce the double helical array of B-DNA and we show their strong potential at selectively inhibiting DNA-binding enzymes of therapeutic relevance such as Topoisomerase 1 and HIV-1 integrase[7]. Thanks to the high modularity of the foldamers structure and their differences from DNA, such molecules provide a versatile platform to conceive novel inhibitors of protein-DNA interactions.
Figure 1. Structural comparison of a 16-mer foldamer (a) and an 8-base pair B-DNA duplex (b).
References [1] R. Rohs, X. Jin, S. M. West, R. Joshi, B. Honig, R. S. Mann, Annu. Rev. Biochem. 2010, 79, 233. [2] N. M. Luscombe, S. E. Austin, H. M. Berman, J. M. Thornton, Genome Biol. 2000, 1, reviews001.1. [3] H. C. Wang, C. H. Ho, K. C. Hsu, J. M. Yang, A. H. Wang, Biochemistry 2014, 53, 2865. [4] D. Yüksel, P. R. Bianco, K. Kumar, Mol. BioSyst. 2016, 12, 169. [5] P. E. Nielsen, M. Egholm, R. H. Berg, O. Buchardt, Science 1991, 254, 1497. [6] A. A. Koshkin, S. K. Singh, P. Nielsen, V. K. Rajwanshi, R. Kumar, M. Meldgaard, C. E. Olsen, J. Wengel, Tetrahedron 1998, 54, 3607. [7] K. Ziach, C. Chollet, V. Parissi, P. Prabhakaran , M. Marchivie , V. Corvaglia , P. P. Bose , K. L.-Reddy, F. Godde, J.-M. Schmitter, S. Chaignepain, P. Pourquier , I. Huc, Nat. Chem. 2018, 10, 511.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL4
Synthetic polymer xenoproteins
Bradley L. Pentelute
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA. [email protected]
Over the past 4 years, we have focused on discovering protein-like structures with novel functions. Currently, we are in the midst of developing a platform that enables the discovery and development of synthetic polymers with protein-like structures and functions that are engineered to perform in a wide range of environments (Figure 1). We refer to these compounds as xenoproteins. We are designing xenoproteins to have minimal immunogenicity, stable to extreme temperatures (both hot and cold), and resistant to natural proteases. Structurally, we design these species to feature tunable and well-defined three-dimensional topologies with chemically adjustable properties and on- demand control using selective chemical stimuli. We have developed a discovery engine called RapidX9 (Rapid discovery of xenoproteins from 109 member libraries) to discover functional xenoproteins. We have focused our efforts on the on the discovery of xenobodies (xenoprotein binders). Our xenoprotein scaffolds are inspired by small disulfide rich microproteins (30–50 residues) commonly found in snails, snakes, spiders, and several classes of plants. To discover novel xenoproteins, we build large one-bead-one-compound 109 libraries, fold each xenoprotein, select for function, and as a final step use advanced MS to identify hits. We then chemically synthesize the hit and study its structure and function using a flow technology for the rapid synthesis and scale-up of the discovered variants invented in our lab. To move beyond Nature, we focus on the use of amino acid building blocks that have the opposite chirality of their natural congeners. Amide bonds linking these D-amino acids and resultant mirror-image xenoproteins will be completely invisible to the proteolytic machineries. To date, we have shown that the RapidX9 platform works. We have built complex xenoproteins comprised entirely of abiotic amino acids and shown that they indeed do fold into defined 3D-topologies, which we design to be stabilized by three disulfide bonds. Subsequently, we have devised FACS methods to screen for hits. Last, with considerable effort we have established mass spec methods for the de novo sequencing of each identified variant.
Figure 1. Synthetic polymer xenoproteins. A) The Rapid Identification of Xenoproteins from Billion Member Libraries (RapidX9) platform workflow to discover functional variants that mimic antibodies. B) The first generation scaffold is based on a 3-disulfide linked knottin scaffold with a diversity region on the N-terminus.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL5
Peptide-oligourea hybrid foldamers and ureidopeptides as new modalities in drug discovery
Juliette Fremaux,a Claire Venin,a Laura Mauran,a Jérémie Buratto,b Robert Zimmer,a Florian Koensgen,c Didier Rognan,c Gilles Guichard,*b Sébastien R. Goudreau*a
aUREkA – ImmuPharma Group; 2, rue Robert Escarpit, 33607 Pessac (France), bUniversité de Bordeaux, CBMN, URM 5248; Institut Européen de Chimie et de Biologie; 2, rue Robert Escarpit, 33607 Pessac (France), cFaculté de Pharmacie; 74, route du Rhin, 67401 Illkirch-Graffenstaden (France) [email protected] [email protected]
Peptides have gained so much attention in the last decade that they are now part of the main strategies, with small molecules and biologics, for developing new medicines. This is remarkable knowing that peptides still suffer from important limitations such as poor membrane permeability and short in vivo half-lives. Many efforts have been invested in foldamer research to address those weaknesses in the hope of finding an alternative to peptides or of further improving peptides of current therapeutic interest.[1–3] Oligoureas are in the limited list of such potential foldamers as they offer a good similarity to peptides.[4] Here we described the development of the URELIXTM technology and its application for developing new medicines. Our research led to new peptide-oligourea hybrids and ureidopeptides with improved pharmaceutical properties. Such improvement should facilitate the challenging task of targeting protein-protein interactions (PPIs) and should lead ultimately to new therapeutic applications.
Figure 1. UrelixTM technology: foldamer biomimetics to improve peptides of therapeutic interest.
References [1] M. Pasco, C. Dolain, G. Guichard, in Compr. Supramol. Chem. II, Elsevier, 2017, pp. 89–125. [2] J. W. Checco, S. H. Gellman, Curr. Opin. Struct. Biol. 2016, 39, 96–105. [3] L. M. Johnson, S. H. Gellman, in Methods Enzymol., Elsevier, 2013, pp. 407–429. [4] J. Fremaux, L. Mauran, K. Pulka-Ziach, B. Kauffmann, B. Odaert, G. Guichard, Angew. Chem. 2015, 127, 9954– 9958.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL6
Piling Up Polycyclic Aromatic Hydrocarbons: Stacks, Foldamers and Supramolecular Polymers with Enhanced Conductances
A. Mateo-Alonsoa
aPOLYMAT, University of the Basque Country UPV/EHU. Avenida de Tolosa 72, E-20018 Donostia-San Sebastián, Spain. b) Ikerbasque, Basque Foundation for Science. Bilbao, Spain. [email protected]
Self-assemblying processes play a crucial role in the development of function in biomacromolecules. Recreating this feature on synthetic systems would not only allow understanding and reproducing biological functions but also developing new functions that align with our technological needs. This has inspired the development of mechanically-interlocked systems and conformationally-ordered synthetic oligomers and polymers (known as foldamers). These systems are able to adopt specific conformations through non-covalent intramolecular interactions encoded in their structure. We have developed a new strategy to pile up acenes and azaacenes by a combination of intramolecular hydrogen bonds and aromatic interactions, leading to a new family of mixed-stacks, foldamers and supramolecular polymers. Such process allows piling up aromatic moieties in stacks opening up an efficient charge transport channel.
Figure 1. Charge transport channel of a π-folded molecular junction.
References [1] M. Carini, M. P. Ruiz, I. Usabiaga, J. A. Fernández, E. J. Cocinero, M. Melle-Franco, I. Diez-Perez, A. Mateo- Alonso “Exceptionally High Conductances in π-Folded Molecular Junctions” Nature Commun. 2017, 8, 15195. [2] C. Gozalvez, J. L. Zafra, A. Saeki, M. Melle-Franco, J. Casado and A. Mateo-Alonso “Self-Assembled Mixed- Stacks of Acene Derivatives: From Supramolecular Intercalation to 1D Solids”, Submitted.
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Symposium on Foldamers Bordeaux 2018 Keynote Lecture KL2
Chemical Design of Functional Protein Assemblies
F. Akif Tezcan
aUniversity of California, San Diego [email protected]
Proteins represent the most versatile molecular building blocks available to living organisms or the laboratory scientist for the construction of functional materials and molecular devices. Underlying this versatility is an immense structural and chemical heterogeneity that renders the programmable self-assembly of proteins a difficult design task. To circumvent the challenge of designing extensive non-covalent interfaces for controlling protein self-assembly, we have endeavoured to use chemical bonding strategies based on fundamental principles of inorganic and supramolecular chemistry. These strategies have resulted in discrete or infinite, 1-, 2- and 3D protein architectures that display crystalline structural order yet are highly dynamic and stimuli-responsive, leading to new emergent chemical/physical properties. This presentation will focus on some of the recent, artificial protein assemblies constructed in our laboratory.
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Symposium on Foldamers Bordeaux 2018 Plenary Lecture PL2
Evolution of Sequence-Defined Highly Functionalized Nucleic Acid Polymers
David R. Liu
Broad Institute of Harvard and MIT, Harvard University, Howard Hughes Medical Institute [email protected]
The evolution of sequence-defined synthetic polymers made of building blocks beyond those compatible with polymerase enzymes or the ribosome has the potential to generate new classes of receptors, catalysts, and materials. In the first part of this lecture I will describe a ligase-mediated DNA-templated polymerization system and in vitro selection to evolve highly functionalized nucleic acid polymers (HFNAPs) made from 32 building blocks containing eight chemically diverse side- chains on a DNA backbone. Through iterated cycles of polymer translation, selection, and reverse translation, we discovered HFNAPs that bind PCSK9 and IL-6, two protein targets implicated in human diseases. Mutation and reselection of an active PCSK9-binding polymer yielded evolved polymers with high affinity (KD = 3 nM). This evolved polymer potently inhibited binding between PCSK9 and the LDL receptor. Structure-activity relationship studies revealed that specific side- chains at defined positions in the polymers are required for binding to their respective targets. These findings expand the chemical space of evolvable polymers to include densely functionalized nucleic acids with diverse, researcher-defined chemical repertoires. In the second part of this lecture, I will describe our efforts to illuminate experimentally the relationship between the side-chains available to a biopolymer population and the potential functions of the resulting polymers. Using seven different sets of chemically diverse charged, polar, and nonpolar side-chains, we performed cycles of artificial translation, in vitro selection, and replication on libraries of random side-chain-functionalized nucleic acid polymers, each containing trillions of different sequences and up to 15 side chains per polymer molecule from eight possibilities. We monitored the performance of the seven polymer libraries as they were subjected to Darwinian selections in parallel for binding to either PCSK9 or IL-6 protein. Polymer library sequence convergence levels, bulk population target binding, enrichment levels of individual polymers, and head-to-head competition among the seven post-selection libraries collectively indicate that polymer libraries with nonpolar side-chains outperformed libraries that lacked access to nonpolar side-chains. Access to polar or charged side-chains, in contrast, did not correlate with polymer library performance. Together, these results suggest that the presence of nonpolar groups, resembling functionality present in proteins but missing from natural nucleic acids, may be strong determinants of biopolymer binding activity. This factor may contribute to the apparent evolutionary advantage of proteins over their nucleic acid precursors for some molecular recognition tasks.
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Symposium on Foldamers Bordeaux 2018 Keynote Lecture KL3
Bifunctional Foldamer Catalysis
Samuel H. Gellman
Department of Chemistry, University of Wisconsin, Madison, WI 53706 USA [email protected]
The broad range of activities displayed by the "biofoldamers," proteins and RNA, establishes a set of functional goals to be approached with synthetic foldamers. Enzymes and ribozymes catalyze diverse reactions, often with extraordinary accelerations relative to background rates. The mechanisms by which rates are enhanced vary depending upon the reaction that is catalyzed, and a full accounting for enzymatic rate accelerations remains a subject of debate. Nevertheless, key principles are evident that suggest paths toward development of synthetic foldamer catalysts. Most enzyme active sites present arrays of reaction-facilitating functional groups that are spatially organized for coordinated action on the substrate(s). Our search for new foldamer catalysts focuses on achieving an optimal arrangement of just two reaction groups, i.e., optimal bifunctional catalysis. In initial studies, we have used a crossed aldol reaction, in which formaldehyde is the obligate electrophile, to assay alternative arrangements of pairs of pyrrolidine units presented by distinct β- and α/β-peptide helices.[1] The most effective foldamers contained an αββ backbone repeat with i,i+3 spacing between pyrrolidine-based β residues. Mechanistic analysis supports a catalytic cycle the features covalent activation of both substrates (Figure 1). Subsequent work has probed the versatility of related bifunctional foldamers in reactions that form carbon-carbon bonds.
Figure 1. Proposed mechanism for a foldamer-catalyzed crossed aldol reaction.
Reference [1] Z. C. Girvin, S. H. Gellman J. Am. Chem. Soc. 2018, in press.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL7
Computer Led Design of Functional Arylamide Foldamers
Vojislava Pophristic,a Zhiwei Liu,a Spadanana Makeneni,a Shadi Houshyar Azara, Edwin Carl Flucka
aDepartment of Chemistry & Biochemistry and West Center for Computational Chemistry & Drug Design, University of the Sciences, 600 South 43rd Street, Philadelphia, PA 19104 [email protected]
With the growing number of new structures and potential applications of arylamide foldamers, computational approaches that can efficiently lead the design of function have become increasingly beneficial. Drawing on our effort on the force field reparametrization and protocol development that allow accurate prediction of structures and solution dynamics of arylamide foldamers by molecular dynamics (MD) simulations,[1] we tackled design of foldamer structures for various functions in the following areas. (1) Carbohydrates hold a great promise for health-related diagnostic, detection, therapeutic and research applications. Arylamide foldamer based receptors have been recently shown to have unprecedented selectivity towards sugars,[2] and thus became the focus of our computational study. We will report our progress on computational design of foldamer capsules for monosaccharides and sugar alcohols. (2) We will present our computer led design of helical arylamide foldamers for selective water transport. Our preliminary MD simulations data predict that helical arylamide channels built from only a limited set of building blocks are capable of transporting water at a sufficiently high rate. An initial set of foldamer channels with similar outer diameter but slight different inner channel structural patterns display interesting structure-function relationships. (3) We will also present a study on cyclic oligomers in which computational methods are used for successful structure prediction, as well as for elucidation of conformational interconversion mechanism at the molecular level.
Figure 1. A helical arylamide foldamer highlighting two oxidized naphthyridine residues which anchor a hexanediol molecule to the inner capsule wall (top and side views).
References [1] Z. Liu, A. M. Abramyan, V. Pophristic, New J. Chem. 2015, 39, 3229-3240. [2] N. Chandramouli, Y. Ferrand, G. Lautrette, B. Kauffmann, C. D. Mackereth, M. Laguerre, D. Dubreuil and I. Huc, Nature Chem., 2015, 7, 334.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL8
Developing applications for Molecular Lego with in silico Evolution
Christian Schafmeister
Temple University [email protected]
My group has developed a modular approach to constructing macromolecules with controlled shape and functionality. We synthesize stereochemically pure, functionalized building blocks and assemble them through pairs of amide bonds to create macromolecules with programmable shape and function.1 We are developing applications for these molecules as catalysts and atomically precise membranes. We have developed a programming environment that enables computational evolution of these molecules. This software environment allows every stage of molecular modeling to be automated and can be applied to any foldamers to facilitate modeling and molecular design.
References [1] Northrup, J. D., Mancini, G., Purcell, C. R., and Schafmeister, C. E. Journal Of Organic Chemistry 2017, 82, no. 24, 13020–13033.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL9
Studies on Glycosylated Sugar Amino Acid Foldamers
Kiran Kumar Pulukuri,a Yashoda Krishna Sunkari,a,b Ravi Sankar Ampapathia and Tushar Kanti Chakrabortya,b
aCSIR-Central Drug Research Institute, Lucknow 226031, India bDepartment of Organic Chemistry, Indian Institute of Science, Bengaluru 560012, India [email protected]
Carbohydrate-protein interactions play very crucial roles in many biological processes. Most pathogens use carbohydrate-binding proteins to invade tissues by attaching to the sugar moieties present on the host cell surfaces and vice versa. Although simple monomeric sugars can block such binding sites on pathogens, individual protein–carbohydrate interactions are known to be quite weak and only simultaneous binding of multi-ligands can ensure any effective inhibition. Our continued works on sugar amino acids (SAA) and related building blocks have led to the discovery of many useful molecules, especially SAA-based foldamers with well-defined three- dimensional structures that offer an ideal platform for precise exposition of carbohydrates at the periphery of their rigid backbone resulting in a shape persistent synthetic model capable of mimicking the naturally occurring biological glycopeptides. Glycosylation of SAA-derived foldamers has shown remarkable modulation of the conformational behavior of the native foldamer backbone and these differences were reflected in the contrasting interactions of the resulting glycofoldamers with various biological targets suggesting that the differences in activities may have their seeds in the underlying conformational preferences of these neoglycopeptides.[1] Further, we have studied the influence of linker length[2] and appended sugars[3] on conformational preferences of glycosylated sugar amino acid foldamers and shown that both linker length and appended sugar indeed play a defining role to induce preferred conformations on these glycopeptide backbones. Research activities in our lab in some of these areas will be presented.
References [1] A. Siriwardena, K. K. Pulukuri, P. S. Kandiyal, S. Roy, O. Bande, S. Ghosh, J. M. G. Fernàndez, F. A. Martin, J.- M. Ghigo, C. Beloin, K. Ito, R. J. Woods, R. S. Ampapathi, T. K. Chakraborty, Angew. Chem., Int. Ed. 2013, 52, 10221-10226; [2] Y. K. Sunkari, F. Alam, P. S. Kandiyal, S. Aloysius, R. S. Ampapathi, T. K. Chakraborty, ChemBioChem 2016, 17, 1839-1844; [3] Y. K. Sunkari, K. K. Pulukuri, P. S. Kandiyal, J. Vaishnav, R. S. Ampapathi, T. K. Chakraborty, ChemBioChem 2018, 19, 1507-1513.
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Symposium on Foldamers Bordeaux 2018 Keynote Lecture KL4
Expressions of Cooperativity in the Synthesis and Properties of Porphyrin Nanorings
Harry L. Anderson
University of Oxford, Department of Chemistry, Oxford OX1 3TA, United Kingdom [email protected]
Cooperative supramolecular interactions can be exploited in the template-directed synthesis of porphyrin nanorings, such as the Russian doll complex shown in Figure 1.[1-3] These macrocycles have huge affinities for their templates, due to strong multivalent chelate cooperativity, as quantified by the effective molarity. They have diameters in the range 2–20 nm, well into the domain of proteins, and their supramolecular assembly properties mimic some of the features of proteins.[2,3] They also display cooperative electronic effects, such as excited state delocalization and global aromatic ring currents.[4-6]
N N Zn N N N N N Zn N N N N N N N N Zn N N N N Zn N O O N N N N N N Al N N N N O N Zn N N N N O N O N N N Al Al N N N N O N Zn N N N N N N N
N N N N N Zn N N N N N N O Al Al N N N N O N N O N N N Zn N O N N N N Al N N N N N N O O N Zn N N N N N N N Zn N N N N N N N N Zn N N Zn N N
Figure 1. Structure of a Russian doll nanoring complex.[3]
References [1] M. C. O’Sullivan, et al., Nature 2011, 469, 72. [2] D. V. Kondratuk, et al., Nature Chem. 2015, 7, 317. [3] S. A. L. Rousseaux, et al. J. Am. Chem. Soc. 2015, 137, 12713. [4] C.-K. Yong, et al., Chem. Sci. 2015, 6, 181–189. [5] M. D. Peeks, et al., J. Am. Chem. Soc. 2017, 139, 10461. [6] M. D. Peeks, et al., Nature 2017, 541, 200.
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Symposium on Foldamers Bordeaux 2018 Keynote Lecture KL5
Communication through Noncovalent Networks
Marcey L. Waters
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 [email protected]
Proteins utilize large complex networks of noncovalent interactions to define form and function. Communication through these networks results in complex behavior such as catalysis, allostery, and signal transduction. While studies of a few proteins has allowed for detailed mechanistic understanding of these phenomena, in many cases the proteins are too complex to determine the molecular mechanisms. We will describe a synthetic catenane that demonstrates long-distance communication through a network of noncovalent interactions as a model for allostery and signal transduction, and define the molecular mechanisms which allow for this structural perturbation.[1], [2], [3]
Figure 1. Stimulus-responsive catenane via communication through a noncovalent network
References [1] M.-K. Chung, P. S. White, S. J. Lee, M. R. Gagné*, M. L. Waters*, J. Am. Chem. Soc., 2016, 138, 13344–13352. [2] M.-K. Chung, P. S. White, S. J. Lee, M. L. Waters*, .M. R. Gagné*, J. Am. Chem. Soc. 2012, 134, 11415–11429 [3] M.-K. Chung, S. J. Lee, M. L. Waters*, .M. R. Gagné*, J. Am. Chem. Soc. 2012, 134, 11430–11443.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL10
Higher-order peptide nanostructures via metal-induced folding and assembly
Tomohisa Sawada,a and Makoto Fujita a,b
aSchool of Engineering, The University of Tokyo, bInstitute for Molecular Science [email protected]
Folding and assembly are respectively intra- and inter-molecular processes for spontaneously generating well-defined protein structures in natural systems. However, in synthetic fields, such processes have been utilized independently for constructions of well-defined nanostructures to date. Recently, our research group have developed the folding-and-assembly strategy, in which short peptide fragments can self-assemble into a well-defined nanostructure through concerted processes of folding and assembly triggered by metal coordination. For example, a ditopic ligand of the GPP sequence adopted the polyproline II helix conformation through complexation with Ag(I) ion, which afforded crystalline porous coordination networks.[1,2] The large helical pores (d = 2 nm) were formed via three-dimensional entanglements of polyproline II helix-based coordination polymers. An analogous ligand of the PGP sequnece adopted an Ω-shaped loop upon Ag(I) coordination,[3] which self-assembled to a [4]catenane molecule (Figure 1a).[4] Four equivalent macrocycles formed a tetrahedral link through 12 times strand-crossings in total. Furthermore, we also succeeded in artificial construction of a β-barrel structure by designing the peptide ligand, in which the β-forming FVFV sequence and the PGP loop were linked with an aromatic spacer (Figure 1b).[5] Thus, we propose this new synthetic strategy is powerful for creating higher-order peptide nanostructures.
Figure 1. Formation of (a) a 12-crossing [4]catenane and (b) a β-barrel structure.
References [1] T. Sawada,* A. Matsumoto, M. Fujita,* Angew. Chem. Int. Ed. 2014, 53, 7228. [2] T. Sawada,* M. Yamagami, S. Akinaga, T. Miyaji, M. Fujita,* Chem. Asian J. 2017, 12, 1715. [3] T. Sawada,* Y. Inomata, M. Yamagami, M. Fujita,* Chem. Lett. 2017, 46, 1119. [4] T. Sawada,* M. Yamagami, K. Ohara, K. Yamaguchi, M. Fujita,* Angew. Chem. Int. Ed. 2016, 55, 4519. [5] M. Yamagami, T. Sawada,* M. Fujita,* submitted.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL11
Chiral Symmetry Breaking Exhibited by Racemic Helicene Oligomers
Masahiko Yamaguchi
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Sendai 980-8578 Japan [email protected]
Chiral symmetry breaking is the phenomenon in which an achiral substance is converted to a chiral substance, and an enantiomeric substance predominates. Consider a chemical reaction to produce enantiomers B and ent-B by a bimolecular reaction of an achiral substrate 2A. The reaction generally provides a racemic mixture of B and ent-B. When B or ent-B is predominantly formed, chiral symmetry breaking has occurred. This phenomenon is considered to involve an amplification reaction to produce B or ent-B. Once the amount of one of the enantiomers B (or ent-B) is increased by chiral perturbations, the subtle difference is amplified to form a significant amount of B (or ent-B). Described here is chiral symmetry breaking exhibited by racemic aminomethylene helicene oligomers 1 and oxymethylene helicene oligomers 2 during formation of hetero-double-helices and their self-assembly materials (Figure 1).[1] The phenomenon is derived from the presence of hetero- double-helices with enantiomeric right and left-handed helical structures.[2]
Figure 1. Racemic aminomethylene and oxymethylene helicene oligomers
References [1] Y. Kushida, T. Sawato, M. Shigeno, N. Saito, M. Yamaguchi, Chem. Eur. J. 2017, 23, 327-333. [2] N. Saito, M. Yamaguchi, Molecules, 2018, 23, 277.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL12
Thioamide modifications of the peptide backbone
E. James Peterssona,b
aDepartment of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA bDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA [email protected]
Thioamide modifications of the peptide backbone have been relatively underexplored, but recent investigations have revealed the biosynthetic pathways of several natural thioamide-containing peptides[1,2] and proteins[3] and shown that thioamidation can improve therapeutic peptides.[4] This single atom, oxygen-to-sulfur substitution can have subtle or profound effects on the interactions and reactivity of peptides. Although it maintains both hydrogen bond accepting and donating character, changes to the amide geometry, hydrophobicity, chemical reactivity, optical, and electronic properties allow thioamides to be used as biophysical probes and as a means of improving peptide function. Our laboratory has used thioamides extensively as probes to study protein folding[5,6,7] and, more recently, to stabilize injectable peptides for therapeutic or imaging purposes.[8] This lecture will highlight some of our recent results and discuss their implications for thiocarbonyl modifications, including those in peptidyl natural products and synthetic foldamers.
Figure 1. Applications of thioamide modifications of peptides.
References [1] G. E. Kenney, L. M. K. Dassama, M.-E. Pandelia, A. S. Gizzi, R. J. Martinie, P. Gao, C. J. DeHart, L. F. Schachner, O. S. Skinner, S. Y. Ro, X. Zhu, M. Sadek, P. M. Thomas, S. C. Almo, J. M. B. Jr., C. Krebs, N. L. Kelleher, A. C. Rosenzweig, Science. 2018, 359, 1411. [2] N. Mahanta, A. Liu, S. Dong, S. K. Nair, D. A. Mitchell, Proc. Natl. Acad. Sci. USA. 2018, 115, 3030. [3] D. D. Nayak, N. Mahanta, D. A. Mitchell, W. W. Metcalf, eLife. 2017, 6, e29218. [4] H. Verma, B. Khatri, S. Chakraborti, J. Chatterjee, Chem. Sci. 2018, 9, 2443. [5] E. J. Petersson, J. M. Goldberg, R. F. Wissner, Phys. Chem. Chem. Phys. 2014, 16, 6827. [6] C. R. Walters, D.-M. Szantai-Kis, Y. Zhang, Z. E. Reinert, W. S. Horne, D. M. Chenoweth, E. J. Petersson, Chem. Sci. 2017, 8, 2868. [7] C. R. Walters, J. J. Ferrie, E. J. Petersson, Chem. Commun. 2018, 54, 1766. [8] X. S. Chen, E. Mietlicki-Baase, T. M. Barrett, L. McGrath, L; K. Koch-Laskowski, J. J. Ferrie, M. R. Hayes, E. J. Petersson, J. Am. Chem. Soc. 2017, 139, 16688.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL13
Stabilized Peptides to Target PPIs
Zigang Li,
State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University [email protected]
Continuous efforts have been invested in developing constrained peptides for modulating PPIs by enhancing the peptides’ helicity. A precisely-positioned in-tether chiral centre was found to be able to modulate a peptide’s helicity and cell permeability.[1] This chirality induced helicity(CIH) concept was then translated into a N-terminus aspartic acid linkage(TD) for more facile peptide synthesis.[2] The stabilized peptides constructed with these methods were utilized to target different intracellular protein targets including MDM2 and ERα, both in vitro and in vivo.[3,4,5] Notably, PROTAC strategy could also be applied with stabilized peptides.[5]
Figure 1. Stabilized peptides to target intramolecular PPIs.
References [1] Hu, K.; Geng, H.; Zhang, Q.; Liu, Q.; Xie, M.; Sun, C.; Li, W.; Lin, H.; Jiang, F.; Wang, T.; Wu, Y.; Li, Z. Angew. Chem.Int. Ed. 2016, 55, 8013-8017. [2] Zhao, H.; Liu, Q.; Geng, H.; Tian, Y.; Cheng, M.; Jiang, Y.; Xie, M.; Niu, X.; Jiang, F.; Zhang, Y.; Lao, Y.; Wu, Y.; Xu, N.; Li, Z. Angew. Chem. Int. Ed. 2016, 55, 12267–12272. [3] Hu, K.; Yin, F.; Yu, M.; Sun, C.; Li, J.; Liang, Y.; Li, W.; Xie, M.; Lao, Y.; Liang, W.; Li, Z. Theranostics 2017, 9, 4566-4576. [4] Xie, M.; Zhao, H.; Liu, Q.; Zhu, Y.; Feng, Y.; Liang, Y.; Jiang, Y.; Wang, D.; Hu, K.; Qin, X.; Wang, Z.; Wu, Y.; Xu, N.; Ye, X.; Wang, T.; Li, Z. J. Med. Chem. 2017, 60, 8731-8740. [5] Jiang, Y.; Deng, Q.; Zhao, H.; Xie, M.; Chen, L.; Yin, F.; Qin, X.; Zheng, W.; Zhao, Y.; Li, Z. ACS Chem. Bio. 2018, 13, 628-633.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL14
Helical Foldamers Based on the Conformational Properties of Aromatic Amides
Aya Tanatani,a Ko Urushibara,a Hyuma Masu,b Isao Azumaya,c Hiroyuki Kagechikad
a Natural Science Division, Faculty of Core Research, Ochanomizu University, bCenter for Analytical Instrumentation, Chiba University, cFaculty of Pharmaceutical Sciences, Toho University, bInstitute of Biomaterials and Bioengineering, Tokyo Medical and Dental University. [email protected]
Aromatic secondary amides such as benzanilide exist in trans form, whereas N-alkylated benzanilides exist in cis form in the crystal and predominantly in cis form in solution.[1] Similarly, aromatic N,N’- dialkylated ureas and squaramides[2] exist in the folded (cis, cis) conformations (Fig. 1a). The cis conformational preference of these molecules can be applied to construct the aromatic helical foldamers with unique conformational properties, such as poly(N-alkylated p-benzamide)s.[3] In this study, we designed and synthesized novel helical foldamers, based on the cis conformational properties of amide and squaramide bonds. First, we examined the conformational properties of N- alkylated pyrrole-[4] and imidazoleamides and their oligomers in order to clarify the generality of cis conformational preference of N-alkylated amides. In the case of the N-methylated imidazoleamides, the conformational alteration was observed by addition of acid. Second, we designed and synthesized the alternately N-alkylated aromatic oligoamides 1 (Fig. 1b) as the helical foldamers with larger cavities, compared to those of poly(N-alkylated p-benzamide)s. NMR and CD spectroscopic studies and calculated optimized structures showed that the oligomers existed in the helical structures with about 9 Å of diameter of the cavity. Finally, we applied the chemical properties of aromatic squaramides to the aromatic architechture.[5] Interestingly, the frequent formations of the chiral crystals of N,N’-bis(ortho-substituted phenyl)squaramides were observed with various types of one- handed helical structures (Fig. 1c). Thus, aromatic N-alkylated amide and related functional groups with cis conformation is useful building block for unique aromatic foldamers.
Figure 1. (a) Conformational properties of aromatic amide and squaramide; (b) Structures of the alternately N-alkylated aromatic oligoamides 1; (c) Helical structure of N,N'-diarylsquaramide
References [1] Tanatani, A.; Yamaguchi, K.; Azumaya, I.; Fukutomi, R.; Shudo, K.; Kagechika, H. J. Am. Chem. Soc. 1998, 120, 6433-6442. [2] Muthyala, R.S.; Subramaniam, G.; Todaro, L. Org. Lett. 2004, 6, 4663-4665. [3] Tanatani, A. Yokoyama, I. Azumaya, Y. Takakura, C. Mitsui, M. Shiro, M. Uchiyama, A. Muranaka, N. Kobayashi,; T. Yokozawa, J. Am. Chem. Soc. 2005, 127, 8553-8561. [4] Tojo, Y.; Urushibara, K.; Yamamoto, S.; Mori, H.; Masu, H.; Kudo, M.; Hirano, T.; Azumaya, I.; Kagechika, H.; Tanatani, A. J. Org. Chem. 2018, 83, 4606-4617. [5] Park, S.; Uchida, J.; Urushibara, K.; Kagechika, H.; Kato, T.; Tanatani, A. Chem. Lett. 2018,17, 601-604.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL15
Rationally designed antimicrobial foldamers against antibiotic resistance
Gábor Olajos,a Réka Spohn,b Ana Martins,b Csaba Pál,b Tamás A. Martinekc
a Institute of Pharmaceutical Analysis, University of Szeged, b Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, c Department of Medical Chemistry, University of Szeged [email protected]
The acceleration of antibiotic resistance is a global threat according to the WHO. Recently, we found that antimicrobial peptides (AMP-s) induce collateral sensitivity in diverse resistant strains[1], but their application as drugs is limited because of the poor pharmacokinetic properties and proteolytic instability. Our goal was to enhance the proteolytic stability of a lead AMP, PGLA[2] while retaining its advantageous collateral sensitivity profile. According to MD simulations, the mechanism of folding in the presence of the membrane is governed by the desolvation of clustered alanine residues. We designed three analogs with homologous 3-amino acid replacement patterns based on the level of desolvation. (Figure 1.)
Figure 1. Replacements patterns of foldameric PGLA analogs.
In accordance with the simulations, replacing the alanine keel of the peptide (B3) resulted in the loss of activity, while the other analogs (B1 and B2) had comparable activity with the parent sequence. Collateral sensitivity experiments carried out on 60 resistant E. coli strains showed that the two active analogs retained PGLA’s sensitivity profile and the number of cross-resistant strains remained low. The proteolytic stability against trypsin and Proteinase K was increased by several magnitudes, up to complete resistance against trypsin in case of analog B1.
References [1] V. Lázár et al. Nature Microbiology 2018, 3, 718. [2] G. Giovannini, L. Poulter, B.W. Gibson, D.H. Williams Biochem. J. 1987, 234, 113.
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Symposium on Foldamers Bordeaux 2018 Plenary Lecture PL3
DNA Nanostructures for Cellular Delivery of Therapeutics
Hanadi Sleiman
Department of Chemistry, McGill University. [email protected]
DNA nanotechnology has emerged as an exceptionally programmable method to organize materials. Most current strategies rely on assembling a complex DNA scaffold, often containing hundreds of different strands, and using it to position materials into the desired functional structure. Our research group has developed a different approach to build DNA nanostructures. Starting from a minimum number of DNA components, we create 3D-DNA host structures, such as cages, nanotubes and spherical nucleic acids, that are promising for targeted drug delivery. These can encapsulate and selectively release drugs and materials, and accomplish anisotropic 3D-organization. We find that they resist nuclease degradation, silence gene expression to a significantly greater extent than their component oligonucleotides and have a favorable in vivo distribution profile. We designed a DNA cube that recognizes a cancer-specific gene product, unzips and releases drug cargo as a result, thus acting as a conditional drug delivery vehicle; as well as DNA structures that bind to plasma proteins with low nanomolar affinities, thus increasing stability in vivo. We will also describe a method to ‘print’ DNA patterns onto other materials, thus beginning to address the issue of scalability for DNA nanotechnology. Finally, we will discuss the ability of small molecules to reprogram the assembly of DNA, away from Watson-Crick base-pairing and into new motifs.
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Symposium on Foldamers Bordeaux 2018 Plenary Lecture PL4
Searching for Selective Reactions in Complex Molecular Environments with Peptide-Based Catalysts
Scott J. Millera aDepartment of Chemistry, 225 Prospect Street, Yale University, New Haven, CY 06520-8107 USA [email protected]
This lecture will describe recent developments in our efforts to develop low-molecular weight, peptide-based catalysts for asymmetric reactions. Over time, our view of asymmetry has ebbed and flowed, with foci on enantioselectivity, site-selectivity and chemoselectivity. In most of our current work, we are studying issues of enantioselectivity as a prelude to extrapolation of catalysis concepts to more complex stereochemical settings where multiple issues are presented in a singular substrate.[1] Moreover, we continuously examine an interplay between screening of catalyst libraries and more hypothesis-driven experiments that emerge from screening results. Some of the mechanistic paradigms, and their associated ambiguities, will figure strongly in the lecture. An overarching theme will be the correlations between peptide-based catalyst structure and associated function in terms of the catalytic reactions.[2] O R2 R NH 2 N O R2 H R2 NH N N H N O R2 Me SH R NH 2 N H O R2 O R2 NH H N O O H P Ph Ph
O R2 O R2 R NH R NH 2 N 2 N H H N Me Me N
O R2 O R R2 NH 2 N R NH H 2 N H O S Me O P N OH O Et BnO O R2 R2 R3 R NH N 2 N H H O N N CF3 HN N
Figure 1. A range of peptide-based catalysts is being explored for the capacity to mediate enantioselective and site-selective reactions.[3]
References [1] “Applications of Non-Enzymatic Catalysts to the Alteration of Natural Products” C.R. Shugrue and S. J. Miller Chem. Rev. 2017, 117, 11894-11951. [2] “Diversity of Secondary Structure in Catalytic Peptides with beta-Turn-Biased Sequences” A. J. Metrano; N. C. Abascal; B. Q. Mercado; E. K. Paulson; A. E. Hurtley; S. J. Miller J. Am. Chem. Soc. 2017, 139, 492-516. [3] For one representative recent example, see: “Divergent Control of Point and Axial Stereogenicity: Catalytic Enantioselective C−N Bond-Forming Cross-Coupling and Catalyst-Controlled Atroposelective Cyclodehydration” Y. Kwon; A. J. Chinn; B. Kim; S. J. Miller Angew. Chem. Int. Ed. 2018, 57, 6251-6255.
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Symposium on Foldamers Bordeaux 2018 Keynote Lecture KL6
Functionalizing helical -peptoids
Christian A. Olsen
Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark [email protected]
Non-natural peptide analogs have significant potential for development of new materials and pharmacologically active ligands. Using one such architecture, the -peptoids (N-alkyl--alanines), we have developed promising antimicrobial and cell-penetrating peptidomimetics.[1] The folding propensity of this backbone, however, was sparsely studied and we therefore investigated the effect of structural variations on the cis–trans amide bond rotamer equilibria in model systems. These experiments revealed new insight into stabilization of conformations through carbonyl-carbonyl interactions.[2,3] Based on the principles revealed by these model systems, we were able to design the first helical -peptoid oligomers, characterized by X-ray diffraction crystallography.[4] Thus, despite their backbone flexibility, -peptoids containing N-(S)-1-(1-naphthyl)ethyl (Ns1npe) side chains can fold into unique triangular prism-shaped helices. However, addition of functional groups would be necessary to enable applications of these foldamers and this has now been achieved in our laboratory. Thus, the lecture will focus on the recent, unpublished, efforts to introduce amino groups onto robustly folded -peptoid helices by construction and incorporation of novel chiral building blocks. We envision that this novel foldamer may serve as an interesting scaffold for multivalent display with high accuracy or for generation of supramolecular assemblies.
References [1] C. A. Olsen. ChemBioChem 2010, 11, 152. [2] J. S. Laursen, J. Engel-Andreasen, P. Fristrup, P. Harris, C. A. Olsen. J. Am. Chem. Soc. 2013, 135, 2835. [3] J. Engel-Andreasen, K. Wich, J. S. Laursen, P. Harris, C. A. Olsen. J. Org. Chem. 2015, 80, 5415. [4] J. S. Laursen, P. Harris, P. Fristrup, C. A. Olsen. Nat. Commun. 2015, 6, 7013.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL16
Recent advances in metallopeptoids: electrocatalytic water oxidation and the first examples of metallopeptoid helicates
Galia Maayan
Schulich Faculty of Chemistry, Technion – Israel Institute of Technology, Haifa, Israel [email protected]
Metal-binding peptoids and metallopeptoids are an important class of biomimetic oligomers with demonstrated functionalities including folding,[1] selective recognition[2] and catalysis.[3-4] Here, we will present the first example of metallopeptoid-based water oxidation electrocatalyst, a Cu-peptoid trimer bearing a bipyridine and an –OH groups, which is both highly stable and efficient, enabling oxygen evolution in aqueous phosphate buffer solution at pH 11.5. Based on electrochemical experiments and DFT-D3 calculations we propose a unique intramolecular cooperative catalytic mechanism for this reaction, which is suggested to have a major role in the high stability of the complex. Attempts to characterize this complex in the solid-state, led to its crystallization in acetonitrile. Surprisingly, its X-ray diffraction analysis revealed an exceptional, highly symmetric, cyclic structure formed by the self-assembly of two peptoid molecules with two Cu(II) ions. Replacing the hydroxyl group by either an –OCH3 or an –NH2 groups resulted in the formation of the first examples of aqua-bridged dinuclear double-stranded peptoid helicates, upon copper binding and crystallization (Fig. 1).[5] Spectroscopic and computational data showed that these crystals were re- dissolved in acetonitrile, the macrocycles containing –OH and –OCH3 disassemble to their corresponding monometallic complexes, while the one containing the –NH2 side chain, having the largest amount of intermolecular hydrogen bonds, is stable in solution.[5]
Figure 1. Crystal structures of self-assembled cyclic metallopeptoids showing highly symmetric macrocycle (right) and aqua-bridged (left) dimeric complexes, composed of two peptoid trimers and two Cu2+ ions. The balls representation of the later describes the first dinuclear double-stranded peptoid helicates.
References [1] L. Zborovsky, A. Smolyakova, M. Baskin and G. Maayan, Chem. Eur. J., 2018, 24, 1159 –1167. [2] M. Baskin, G. Maayan, Chem. Sci., 2016, 7, 2809-2820. [3] Prathap, K. J.; Maayan, G. Chem. Commun. 2015, 51, 11096-11099. [4] C. M. Darapanani, A. Sadhukha, G. Maayan, Journal of Catalysis 2017, 355, 139–144. [5] T. Ghosh, N. Fridman, M. Kosa, G. Angew Chem. In press.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL17
MAMBA: A Laterally-Flexible and Functionally Diverse Oligoamide Foldamer
Joseph W. Meisela and Andrew D. Hamiltona
aDepartment of Chemistry, New York University, New York, New York, United States [email protected]
Foldamers have potential applications as organocatalysts,[1] in novel materials,[2] and as biologically active species.[3] Optimal foldamer scaffolds are functionally diverse, synthetically accessible, and conformationally predictable. In an effort to satisfy these requirements, we have designed a densely functionalized scaffold based on a 2,4-dialkoxy-meta-aminomethylbenzoic acid (MAMBA) monomer that folds into a serpentine or ribbon conformation. By utilizing principles commonly applied in solid phase peptide synthesis, MAMBA oligomers can be elongated and functionalized entirely on resin from a single starting material. Two functional groups per monomer are appended by alkylation of phenolic oxygen atoms and the chain is elongated by standard amino acid coupling procedures. Lateral flexibility is achieved by simultaneously disrupting backbone conjugation with a benzylic methylene group and restoring conformational preference with a bifurcated hydrogen bond between main-chain amides and side-chain phenolic ethers. Crystal structure and solution phase NMR data support the hydrogen-bonded conformation, which can mimic β-sheets and β-hairpin turns. Cyclic tetramers and pentamers (called MAMBA[n]arenes) were prepared by solution-phase macrocyclization and were shown to fold into dynamic cavitand structures. Both linear and cyclic oligomers bearing different functional groups can be fragmented and sequenced by MALDI- TOF/TOF mass spectrometry, which enables deconvolution of foldamer libraries. With synthetic methodology and basic conformational characterization in hand, we are now exploring potential applications of the heterofunctionalized MAMBA scaffold in biomolecular recognition.
Figure 1. Chemical structures for linear MAMBA oligomers (left panel) and cyclic MAMBA[4]arenes (right panel) are shown. Capped linear trimers are shown in trans (modeled) and cis (X-ray) conformations in the left panel. MAMBA[4]arene structures are shown in cone (modeled) and 1,2-alternate (X-ray) conformations in the right panel.
References [1] G. Maayan, M. D. Ward, K. Kirshenbaum, Proc. Natl. Acad. Sci. USA 2009, 106, 13679. [2] L. Chen, H. Wang, D-W. Zhang, Y. Zhou, Z-T. Li, Angew. Chem. Int. Ed. 2015, 54, 4028. [3] S. Kumar, A. D. Hamilton, J. Am. Chem. Soc. 2017, 139, 5744.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL18
Acceleration and sense selectivity of amide rotation by side-chain stapling of bicyclic -proline dimers
Xin Liu,a Hisashi Ohno,a Siyuan Wang, a Luhan Zhai, a Aoze Su, a Yuko Otani,a and Tomohiko Ohwada a
a Graduate School of Pharmaceutical Sciences, University of Tokyo,7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. [email protected] and [email protected]
NMR analysis, X- -proline mimic dimers [1, 2] showed that the amide equilibrium changed from the intrinsically favored cis conformation to almost exclusively trans conformation upon side-chain stapling. Stapling constraint also increased the rotational rate of cis to trans conformer and induced selection of sense of rotation: as the ring size decreased, the rotational rate of cis to trans conformer increased. The rigid backbone, steric effect, and the intrinsic nonplanarity of the bicyclic systems[3] amplify the influence of subtle changes in linker length to generate large differences in overall conformation.
Figure 1. Dynamics of amide cis-trans equilibrium of stapled dimers
References [1] M. Hosoya, Y. Otani, M. Kawahata, K. Yamaguchi, T. Ohwada, J. Am. Chem. Soc. 2010, 132, 14780-14789. [2] S. Wang, Y. Otani, X. Liu, M. Kawahata, K. Yamaguchi, T. Ohwada, J. Org. Chem., 2014, 79, 5287-5300. [3] S. Wang, T. Taniguchi, K. Monde, M. Kawahata, K. Yamaguchi, Y. Otani, T. Ohwada, Chem. Commun., 2016, 52, 4018 - 4021.
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Symposium on Foldamers Bordeaux 2018 Keynote Lecture KL7
Out-of-equilibrium Integration of Molecular Machines
Prof. Nicolas Giusepponea
a University of Strasbourg, Institut Universitaire de France (IUF), Institut Charles Sadron - CNRS, 23 rue du Loess, BP 84047, 67034 Strasbourg Cedex 2, France [email protected]
Making molecular machines that can be useful in the macroscopic world is a challenging long-term goal of nanoscience. Inspired by the protein machinery found in biological systems, and based on the theoretical understanding of the physics of motion at the nanoscale, organic chemists have developed a number of molecules that can produce work when triggered by various external chemical or physical stimuli. In particular, basic molecular switches that commute between at least two thermodynamic minima and more advanced molecular motors that behave as dissipative units working far from equilibrium when fueled with external energy have been reported. However, the ultimate challenge of coordinating individual molecular motors in a continuous mechanical process that can have a measurable effect at the macroscale has remained elusive until very recently. We will discuss advances developed by our group on artificial molecular machines and involving their mechanical coupling within dynamic polymer systems. We will show that it is now possible to amplify their individual motions to achieve macroscopic functions in materials. In particular, we will present a dual-light controlled system operating fully out-of-equilibrium, and in which the integrated motions of two types of mechanically active units can be tuned by modulation of frequencies.
References [1] G. Du, E. Moulin, N. Jouault, E. Buhler, N. Giuseppone, Angew. Chem. Int. Ed. 2012, 51, 12504. [2] Goujon, A., Du, G., Moulin, E., Fuks, G., Maaloum, M., Buhler, E., Giuseppone, N., Angew. Chem. Int. Ed. 2016, 55, 703. [3] Goujon, A., Mariani, G., Lang, T., Moulin, E., Rawiso, M., Buhler, E., Giuseppone, N., J. Am. Chem. Soc. 2017, 139, 4923. [4] Goujon, A., Lang, T., Mariani, G., Moulin, E., Fuks, G., Raya, J., Buhler, E., Giuseppone, N., J. Am. Chem. Soc. 2017, 139, 14825. [4] Li, Q., Fuks, G., Moulin, E., Maaloum, M., Rawiso, M., Kulic, I., Foy, J. T., Giuseppone, N., Nature Nanotech. 2015, 10, 161. [5] Foy, J., Li, Q., Goujon, A., Colard-Otté, J.-R., Fuks, G., Moulin, E., Schiffmann, O., Dattler, D., Funeriu, D. P., Giuseppone, N., Nature Nanotech. 2017, 12, 540.
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Symposium on Foldamers Bordeaux 2018 Keynote Lecture KL8
Phage display selection of chemically cyclized peptides for the development of therapeutics
Christian Heinis
Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland [email protected]
My laboratory is engaged in the discovery and development of cyclic peptides for therapeutic application. A major focus is the generation of ligands based on bicyclic peptides by phage display. The bicyclic peptides combine key qualities of antibody therapeutics (high affinity and specificity) and advantages of small molecule drugs (access to chemical synthesis, diffusion into tissue, various administration options). In my talk, I will introduce bicyclic peptide phage display[1], present new chemical reactions that we have applied to generate structurally highly diverse cyclic peptide libraries[2-4], and show recent data on the therapeutic activity of bicyclic peptides in vivo.
Figure 1. (A) Large libraries of random peptides (> 4 billion different peptides) are displayed on phage and cyclised in a chemical reaction (left). Binders to targets of interest are subsequently isolated in affinity selections (right). (B) Chemical structure of an isolated bicyclic peptide.
References [1] Heinis, C., et al., Nature Chemical Biology, 2009, 5, 502. [2] Chen, S., et al., Nature Chemistry, 2014, 6, 1009. [3] Zorzi, A., et al., Nature Communications, 2017, 8, 16092. [4] Kale, S., et al., Nature Chemistry, 2018, 10, 7015.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL19
Helical Polymer Channels
Zeyuan Dong
State Key Laborotary of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, China [email protected]
Natural membrane protein channels are the most important border crossings in living system, which span the cellular lipid bilayers to transport ions and molecules into cells. Sophisticated membrane proteins can inspire the design of advanced artificial channels. Recently, we developed a type of synthetic channels with atomistic precision based on pore-containing helical polymers.[1-3] Facile engineering of inner channel structures can tune the chemical microenvironments, dynamics and interactions with other molecules to a great extent, thus endowing these synthetic channels with the stability and selectivity during transmembrane conduction. Biomimetic functions of helical polymer channels will be considered in real-world applications of nanopores.
Figure 1. Helical polymer channels with transmembrane transport function.
References [1] J. Y. Zhu, Z. Y. Dong, S. B. Lei, L. L. Cao, B. Yang, W. F. Li, Y. C. Zhang, J. Q. Liu, J. C. Shen, Angew. Chem. Int. Ed. 2015, 54, 3097-3101. [2] C. Lang, W. F. Li, Z. Y. Dong, X. Zhang, F. H. Yang, B. Yang, X. L. Deng, C. Y. Zhang, J. Y. Xu, J. Q. Liu, Angew. Chem. Int. Ed. 2016, 55, 9723-9727. [3] C. Lang, X. L. Deng, F. H. Yang, B. Yang, W. Wang, S. W. Qi, X. Zhang, C. Y. Zhang, Z. Y. Dong, J. Q. Liu, Angew. Chem. Int. Ed. 2017, 56, 12668-12671.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL20
Single-molecule force spectroscopy of synthetic foldamers
Anne-Sophie Duwez
University of Liège, Department of Chemistry, B6a Sart-Tilman, 4000 Liège, Belgium. [email protected] - http://www.nanochem.ulg.ac.be
In 1952, Erwin Schrödinger wrote that we would never experiment with just one electron, one atom, or one molecule.[1] Forty years later, methods derived from scanning probe microscopies allowed us to manipulate single atoms and molecules, and even single bonds.[2] Single-molecule force spectroscopy, which consists in trapping and stretching a molecule between an AFM tip and a surface, enables to probe (and/or to induce) molecular processes in situ and in real time through the application of mechanical forces. Such elegant experiments have provided unprecedented insights into the structure and function of many (biological) systems.[3]
Here, we will discuss some of our recent results in the field of AFM-based single-molecule force spectroscopy on synthetic foldamers of oligorotaxanes, polypeptides and aromatic oligoamides. Pulling-relaxing experiments on oligorotaxanes, made of 1,5-dioxynaphthalene donor units incorporated into oligomeric threads and cyclobis(paraquat-p-phenylene) acceptor rings, have revealed the capacity of the molecules to generate a force while folding against a mechanical load. Fluctuations between unfolded and folded states were captured in real-time, evidencing a transition time of less than 10 s, making the folding process as fast as in natural proteins, and remarkably more robust thanks to the interlocked structure. Fluctuations were observed on a wide range of loading rates —103 to 105 pN·s–1, which is 100 to 1000 times higher than those previously tested for biological specimens.[4] Single-molecule force experiments were also performed on two stimuli responsive polymers based on poly(L-glutamic acid) and poly(L-lysine). We investigated the factors that affect the α-helix mechanical stability and observed the folding in real-time under various pH conditions. Finally, we characterized the mechanics of aromatic oligoamide foldamers. We showed that at forces of approximately 100 pN the helix reversibly elongates allowing the molecule to extend to about 2.8 times its original length. This transition is fully reversible, making these synthetic foldamers truly elastic helices. No energy is dissipated and the complete mechanical energy absorbed during the stretching is given back during relaxation. Rapid fluctuations between folded and unfolded states evidenced that the molecules are able to refold against considerable forces of up to 150 pN on a timescale of less than a microsecond. Our results show that aromatic oligoamide foldamers have the potential to exceed the performance of natural helices.
References [1] E. Schrödinger, Br. J. Philos. Sci. 1952, 3, 233. [2] J. K. Gimzewski, C. Joachim, Science 1999, 283, 1683. [3] E. Evans, Annu. Rev. Biophys. Biomol. Struct. 2001, 30, 105 ; C. Bustamante, Y. R. Chemla, N. R. Forde, D. Izhaky, Annu. Rev. Biochem. 2004, 73, 705 ; F. Kienberger, A. Ebner, H. J. Gruber, P. Hinterdorfer, Acc. Chem. Res. 2006, 39, 29 ; J. Liang, J. M. Fernández, ACS Nano 2009, 3, 1628 ; E. M. Puchner, H. E. Gaub, Curr. Opin. Struct. Biol. 2009, 19, 605 ; Molecular Manipulation with Atomic Force Microscopy, Edited by N. Willet and A.-S Duwez, Taylor & Francis group – CRC Press, Boca Raton, USA, 2012, pp. 287. [4] D. Sluysmans, F. Devaux, C. J. Bruns, J. F. Stoddart, A.-S. Duwez, PNAS 2018, DOI: 10.1073/pnas.1712790115 ; D. Sluysmans, S. Hubert, C. J. Bruns, Z. Zhu, J. F. Stoddart, A.-S. Duwez, Nature Nanotech. 2018, DOI: 10.1038/s41565-017-0033-7.
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Symposium on Foldamers Bordeaux 2018 Short Lecture SL21
Self-assembling and functional polyphosphoesters beyond nucleic acids
Christopher J. Serpella
a School of Physical Sciences, Ingram Building, University of Kent, Canterbury, Kent, CT2 7NH, UK [email protected]
The secrets of life are written in the sequences of polyphosphoesters: biology relies upon the capabilities of nucleic acids to store vast quantities of information and catalyse reactions. It is supramolecular chemistry which translates the polymer sequence into structure and function. Recent developments now allow us to use nucleic acids to create functional nanostructures and materials which deviate greatly from those found in nature[1] and at the same time, interest in polyphosphoesters is rising within polymer science due to their biocompatibility and tuneable degradation.[2] There is now an emerging continuum of polymers between DNA and plastics.[3]
Figure 1. Progressive modification of DNA towards self-assembling non-natural polyphosphoesters.
We are working to expand the supramolecular lexicon of polyphosphoesters through the incorporation of news monomers capable of programmed association (Fig. 1). These studies include highly modified DNAs, perfectly sequence-defined non-nucleosidic polyphosphoesters and self- sequencing polycondensation products. We will present investigations into the integration of a range of supramolecular motifs into these phosphodiester polymers to provide fine control of folding,[4] molecular recognition and sensing,[5] looking towards the functions embodied by biological sequence polymers.
References [1] N. C. Seeman, Mol. Biotechnol., 2007, 37, 246–257. [2] T. Steinbach and F. R. Wurm, Angew. Chem. Int. Ed., 2015, 54, 6098–6108. [3] N. Appukutti, C. J. Serpell, Polym. Chem., 2018, 9, 2210-2226 [4] T. G. W. Edwardson, K. M. M. Carneiro, C. J. Serpell and H. F. Sleiman, Angew. Chem. Int. Ed., 2014, 53, 4567– 4571. [5] E. R. Taylor, S. Cavuoto, D. M. Beal, S. Caujolle, A. Podoleanu, C. J. Serpell, ChemRxiv, 2018, DOI: 10.26434/chemrxiv.6086531.v1
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Symposium on Foldamers Bordeaux 2018 Keynote Lecture KL9
Controlling the Folding and Covalent Assembly of ortho-Phenylenes
C. Scott Hartley, Zacharias J. Kinney, Gopi Nath Vemuri
Department of Chemistry & Biochemistry, Miami University, Oxford, Ohio, USA [email protected]
While structurally very simple, o-phenylenes exhibit rich, dynamic conformational behavior in solution.[1] They have been shown to fold into helices in solution because of (offset) arene–arene stacking interactions parallel to the helical axis. o-Phenylene folding is slow on the NMR time scale, and the 1H chemical shifts are both very sensitive to the folding state and readily related to specific geometries. Thus, detailed information on the conformational behavior can be obtained via NMR analysis, especially when combined with computational chemistry.
Although much is now known about why o-phenylenes fold, less has been done to exploit their behavior in more complex chemical systems. This presentation will focus on recent efforts to control the folding of o-phenylenes and to incorporate them within larger architectures. First, we will discuss twist sense control via terminal chiral groups. While similar efforts are well-known in other systems,[2,3] the o-phenylenes provide a very detailed snapshot of the mechanism of chiral induction; for example, we find that the effect of chiral groups is strongly dependent on their positioning relative to the backbone. Second, we discuss efforts to use dynamic covalent chemistry to assemble o- phenylenes into macrocycles.[4,5] The combination of folding with self-assembly under thermodynamic control provides rapid access to twisted architectures of increasing structural complexity, and also raises questions about how folding responds to confinement within macrocycles of different sizes, how communication between folded segments is mediated by linking groups, and how changes to o-phenylene and linker structure affect the size and shape of the products favored at equilibrium.
Figure 1. (a) Folded o-phenylene [12]-mer. (b) o-Phenylene-based twisted macrocycle.
References [1] Hartley, C. S. Acc. Chem. Res. 2016, 49, 646–654. [2] Dolain, C.; Jiang, H.; Leger, J.; Guionneau, P.; Huc, I. J. Am. Chem. Soc. 2005, 127, 12943–12951. [3] Kim, J.; Jeon, H.-G.; Kang, P.; Jeong, K.-S. Chem. Commun. 2017, 53, 6508–6511. [4] Kinney, Z. J.; Hartley, C. S. J. Am. Chem. Soc. 2017, 139, 4821–4827. [5] Kinney, Z. J.; Hartley, C. S. Org. Lett. 2018, 20, 3327–3331.
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Symposium on Foldamers Bordeaux 2018 Plenary Lecture PL5
Helicates and Their Three-dimensional Analogs
Jonathan R. Nitschke
Department of Chemistry, University of Cambridge [email protected]
The dipolar, quadrupolar, and steric effects that lend structure to foldamers can be combined with metal coordination and templation to generate helicates,[1] along with higher-order structures that incorporate helical subunits.[2] This talk will describe the design and uses of some of these three- dimensional architectures, a few of which are shown in Figure 1, as well as the means by which different subunits may communicate stereochemically with each other.
Figure 1. Strange helicates[2-3] and their kin.[4]
References [1] A. M. Castilla, W. J. Ramsay, J. R. Nitschke, Acc. Chem. Res. 2014, 47, 2063-2073. [2] J. L. Greenfield, E. W. Evans, D. Di Nuzzo, M. Di Antonio, R. H. Friend, J. R. Nitschke, J. Am. Chem. Soc. 2018, 140, 10344-10353. [3] D. A. Roberts, B. S. Pilgrim, G. Sirvinskaite, T. K. Ronson, J. R. Nitschke, J. Am. Chem. Soc. 2018, 140, 9616- 9623. [4] (a) F. J. Rizzuto, W. J. Ramsay, J. R. Nitschke, J. Am. Chem. Soc. 2018; (b) F. J. Rizzuto, J. R. Nitschke, Nature Chem. 2017, 9, 903; (c) B. S. Pilgrim, D. A. Roberts, T. G. Lohr, T. K. Ronson, J. R. Nitschke, Nature Chem. 2017, 9, 1276.
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Symposium on Foldamers Bordeaux 2018
Poster Abstracts
45
Symposium on Foldamers Bordeaux 2018 Poster P1
Soluble assemblies of a helical foldamer as selective host for electron deficient organic compounds
Aasheesh Srivastava,a and Rajesh Khowala
aDepartment of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh, INDIA [email protected]
We have designed an electron-rich helical foldamer (HAC)[1] that forms soluble aggregates (HACsa) in chlorinated solvents mainly driven by intermolecular charge transfer interactions (CTI). We noticed unprecedented selectivity of HACsa in accommodating planar electron deficient organic guest 1,2,4,5-tetracyanobenzene (TCNB) through intercalation. TCNB is stabilized within HACsa through CTI that ushers striking visual transformation from yellow to bright red to the solution. Thus, this work lays foundation using helical foldamers for selective CTI-based separation of organic molecules. The color change was also observed upon dry grinding of HAC and TCNB solids together; however, dilution in non-chlorinated solvents and heating reversed it. The complex (HACsaTCNB) had shorter bandgap with large Stokes shifted NIR-emission. The intercalation of TCNB is accompanied by profound structural changes in the molecular arrangement of HAC within the aggregates. On its own, HAC assembles into homochiral helices, while it assembles in heterochiral [2] C2-double helices in the complex. The findings of this work are summarized in Figure 1 below.
Figure 1. Summary of the key observations of the project. The helical foldamer forms soluble aggregates in chlorinated solvents that act as selective host for TCNB. Incorporation of the guest induces strong structural, morphological and photophysical changes in the host.
References [1] R. Kumar, A. Srivastava, Chem. Eur. J. 2016, 22, 3224-3229. [2] R. Kumar, S. Semwal, A. Srivastava, submitted.
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Symposium on Foldamers Bordeaux 2018 Poster P2
Exploring Self-Assembly: Circular Dichroism Studies of Supramolecular Hydrogels
Efstratios Sitsanidis,a Carmen Piras,a Bruce D. Alexander,b Giuliano Siligardi,c Tamas Javorfi,c Andrew J. Hall,a Alison A. Edwardsa
aMedway School of Pharmacy, Universities of Kent & Greenwich at Medway Central Avenue, Chatham, Kent, ME4 4TB, UK. bUniversity of Greenwich, Central Avenue, Chatham, Kent, ME4 4TB, UK. cDiamond Light Source Ltd., Didcot, Oxfordshire, OX11 0DE, UK [email protected]
Low molecular weight (LMW) amphiphiles (gelators) can self-assemble to form viscoelastic solid- like materials (gels) by formation of a three-dimensional fibrous network. These arise due to the non- covalent self-assembly of gelator molecules in water and other biologically relevant media. Our research focuses on (i) the design, synthesis and characterization of novel LMW hydrogelators (LMWHGs) and their corresponding functional biomaterials and (ii) evaluation of their potential applications. We have identified and characterized a number of such molecules which can efficiently gel water (>0.01% w/v). These LMWHGs are composed of monosaccharides, amino acids, drugs, aromatic acids, and/or the ubiquitous Fmoc group. To pursue biological application of these materials, we have prepared our hydrogels using a number of biologically relevant liquid phases, e.g. water, cell culture medium and phosphate buffered saline.
Figure 1: Circular dichroism analysis of hydrogelators and hydrogels.
Many methods to characterize gels rely on characterisation of a bulk sample of the gel and multi-site sampling within the same gel sample is not possible. We have utilized the synchrotron facility at Diamond Light Source to undertake multi-site sampling of hydrogel samples by circular dichroism (CD), which is not possible with commercial instruments.[1] CD is a versatile technique which allows the interaction between chromophores of chiral species to be studied. is especially vital for LMWHGs where, as with peptidic and protein self-assembly, the key interactions for activity or application are through space rather than through bond. This is typified by a negligible CD signal for the solution of a LMWHG and an intense CD signal for the corresponding hydrogel (Figure 1). We have been able to design a series of experiments that allowed evaluation of homogeneity of the hydrogel and the reversibility of hydrogelation, together with observation of the effect of variation to hydrogelator architecture. This characterization methodology will play a key role during application development.
References [1] E. Sitsanidis, C. Piras, B. Alexander, G. Siligardi, T. Javorfi, A. Hall and A. Edwards. Chirality, 2018, 30, 708. 10322.
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Symposium on Foldamers Bordeaux 2018 Poster P3
Synthesis of meso oligourea foldamer built from chiral subunits
Mégane Bornerie,a,b Stéphanie Antunes,a,b Brice Kauffmann,c Céline Douat,a,b,d and Gilles Guicharda,b
aCBMN, UMR 5248, Univ. Bordeaux, All.Goeffroy Saint-Hilaire 33600 Pessac bIECB, Univ. Bordeaux, 2 rue Robert Escarpit 33600 Pessac cIECB, UMS 3033/US 001, Univ. Bordeaux, 2 rue Robert Escarpit 33600 Pessac dDepartment Pharmazie, Ludwig-Maximilians-Universität, Butenandstr 5_13, 81377 München [email protected]
Aliphatic foldamers that typically adopt upon folding helical conformations are most often chiral.[1] Oligoureas composed of chiral ethylene diamine units of type B belong to the peptidomimetic aliphatic foldamer sub-family and exhibit the unique property to fold into well- defined 2.5-helix stabilized through the formation of a H-bond network between the carbonyl and the NH of the ureas in a i, i+2 relationship.[2] Recently, the group of Clayden in collaboration with our group reported that achiral homo- oligourea foldamers built from the meso cyclohexane-1,2-diamine unit A also form stable 2.5-helices. X-Ray structural investigations on these meso foldamers have unveiled that crystals contained both P and M-helices. Variable Temperature 1H-NMR experiments in solution have next enabled the determination of the energy barrier necessary for helix-screw sense inversion. [3]
Concurrently, we have shown that peptidomimetic urea-based foldamers bind strongly to anionic hydrogen-bond acceptors (HBAs). This HBA binding is site specific and mainly involves the NH ureas located at the positive pole of the 2.5-helix.[4] Remarkably, recognition of a chiral anion by the terminal urea of the meso foldamers induces a screw-sense preference by selective coordination of the anion to one of the termini of the meso structure.[3] Herein, we report the first synthesis in solution of meso urea-based foldamers built from chiral acyclic monosubstituted ethylene diamine units B and exhibiting an internal plane of symmetry. X- Ray crystal structures confirmed the presence of both P and M helices in the crystal. More interestingly, breaking the foldamer backbone symmetry by differentiating the end groups induces a preferred helix-screw sense. Moreover, preliminary HBA binding experiments using achiral anions suggest the possibility to modulate the ratio between P- and M-helices by switching the hydrogen bond network and could be used to control helix screw-sense inversion.
References [1] S. Gellman, Acc. Chem. Res, 1998, 31, 173-180 [2] L. Fischer et al., Angew. Chem. Int. Ed, 2010, 49, 1067-1070 [3] R. Wechsel et al.Angew. Chem. Int. Ed., 2016, 55, 9657-9661 [4] V. Diemer et al., Chem. Eur. J, 2016, 22, 15684-15692
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Symposium on Foldamers Bordeaux 2018 Poster P4
Design and Synthesis of Biomimetic β-sheets Ferrocene Derivatives
Yazhou Liu,a Kenji Kopf,a Xiao Mu,a Jérémie Bourotte,a Michael Singleton a
a Place Louis Pasteur 1, bte L4.01.02, 1348 Louvain-la-Neuve, Belgium [email protected]
Well-ordered arrays of functional groups resulting from structural organization (folding) of peptides give rise to the important biological functions of proteins (protein-protein interactions, catalysis, etc….). Their replication could provide a powerful tool in the development of new catalysts and synthetic ligands for the recognition of biological molecules. Aromatic oligoamide foldamers can be a powerful tool towards this goal. While many of these molecules adopt helical structures, a greater surface area for interaction could potentially be provided by sheet-like structures. [1] To this end, ferrocene dicarboxylic acid could be a useful turn-unit in the design of beta-sheet like aromatic oligoamides. The two cyclopentadiene rings in ferrocene are separated by ~ 3.5 Å which provides an optimal separation for pi-pi stacking. However, ferrocene can act as a molecular ball bearing allowing rotation of the strands connected to each ring. Thus, before large sheet-like structures can be developed, the structural stability of molecules using ferrocene as a turn unit must be determined. To study this, we have synthesized a series of aromatic oligoamide strands using monomers with different sized aromatic surfaces and connected them using ferrocene dicarboxylic acid. We then studied their solid state and solution structural behavior with X-ray crystallography and NMR. These efforts and the ability of the ferrocene based aromatic oligoamides to interact with small organic molecules is described.
Figure 1. Schematic representation of ferrocene based aromatic oligoamide foldamer that can bind small organic molecules.
References [1] a. Y. Ferrand, I. Huc, Acc. Chem. Res. 2018, 51, 970-977. b. M. Kudo, D. C. Lopez, V. Maurizot, H. Masu, A. Tanatani, I. Huc, Eur. J. Org. Chem. 2016, 14, 2457-2466. c. N.L. Truex, Y. Wang, J.S. Nowick, J. Am. Chem. Soc. 2016, 138, 13882-13890.
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Symposium on Foldamers Bordeaux 2018 Poster P5
Folding and self-assembly of aromatic oligoamide β-sheets
Joan Atcher,a,b Pedro Mateus,b Brice Kauffmann,b Victor Maurizotb and Ivan Huca,b
aDepartment für Pharmazie, Ludwig-Maximilians-Universität, München, Germany; bUniversité de Bordeaux – CNRS, CBMN (UMR5248), Institut Européen de Chimie et Biologie, Pessac, France [email protected]
The vast majority of foldamers are found to adopt the classical secondary motifs known for biopolymers, namely helices, linear strands, turns and sheet-like structures.[1] Among these, helical foldamers are prevalent while artificial sheets are quite rare. A major difference between these two secondary structures is that helices fulfill their potential for non-covalent interactions intramolecularly, whereas sheets tend to aggregate and precipitate. Thus, the challenge of preparing discrete and soluble β-sheets entails the control of noncovalent interactions so that they operate preferentially in an intramolecular fashion. Following this principle, our group has introduced a first generation of multistranded β-sheet foldamers based on dinitrophenyl short turn units and linear aryl- amide strands (Fig. 1a).[2] The turn holds the aromatic layers in a face-to-face orientation, allowing intramolecular π-π interactions to be strong enough for folding in an organic solvent, but weak enough to prevent aggregation. Additionally, bent aromatic β-sheets have recently been incorporated in an aromatic helical capsule to produce an open molecular receptor.[3]
Figure 1. Crystal structure of aromatic oligoamide β-sheet foldamers consisting of a) three intramolecularly stacked layers, and b) dimeric complex with six intermolecularly stacked layers; c) Top view of the dimer; d) Overlaid snapshots of a 1 ns MD simulation for the dimer at 400 K.
Herein we describe the combined use of the previously mentioned dinitrophenyl short turn with a longer turn based on pyridine-2,6-dicarboxamide. This new turn (in yellow) was designed to promote the self-assembly of two sheets in a discrete dimer by allowing the interdigitation of aromatic layers and also serving as a H-bond donor to stabilize the resulting dimeric complex (Fig. 1b,c). The structural studies of this dimer in solution and in the solid phase revealed a complex dynamic conformational behavior (Fig. 1d). In summary, the present work reports on the successful use of rationally designed self-assembling to produce large but still discrete and soluble aromatic oligoamide β-sheet foldamers. Current efforts in the group are directed towards developing new rigid and polar turn units, as well as polar linear strands, with the aim of bringing aromatic oligoamide β-sheets into water.
References [1] H. S. Chan, K. A. Dill, Annu. Rev. Biophys. Biophys. Chem. 1991, 20, 447. [2] a) L. Sebaoun, V. Maurizot, T. Granier, B. Kauffmann, I. Huc, J. Am. Chem. Soc. 2014, 136, 2168; b) L. Sebaoun, B. Kauffmann, T. Delclos, V. Maurizot, I. Huc, Org. Lett. 2014, 16, 2326. [3] A. Lamouroux, L. Sebaoun, B. Wicher, B. Kauffmann, Y. Ferrand, V. Maurizot, I. Huc, J. Am. Chem. Soc. 2017, 139, 14668.
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Symposium on Foldamers Bordeaux 2018 Poster P6
Supramolecular Strategy to Tubular Nanostructures Self-assembled from Dinucleobase Monomers in Aqueous Media
Fatima Aparicio,a Raquel Chamorro,a Paula Chamorro,a and David González-Rodrígueza
a Nanostructured Molecular Systems and Materials group, Departamento de Química Orgánica, Universidad Autónoma de Madrid, 28049, Madrid, Spain [email protected]
Tube-forming proteins, such as tubulin or aquaporin are fascinating class of self-assembled functional systems found in nature. Driven by their large variety of functions and their nanometer dimensions, scientists are increasingly being attracted to the challenge of designing related nanoscale assemblies. Our project, inspired by these natural systems, aims at establishing a strategy to prepare tubular nanostructures based on complementary dinucleobase monomers featuring an amphiphilic central block, which can self-assemble in aqueous media by diverse noncovalent interactions. Watson-Crick H-bonding[1] produces macrocyclic tetramers[2-6] with a hydrophobic core that can stack through hydrophobic forces to yield the desired nanotubes. On the other hand, the hydrophilic chains oriented to the periphery would help to improve water solubility.
Figure 1. Schematic illustration of the stepwise self-assembly process.
References [1] M. J. Mayoral, C. Montoro-García, D. González-Rodríguez, In Comprehensive Supramolecular Chemistry II, Elsevier: Oxford, 2017; pp. 191-257. [2] C. Montoro-García, J. Camacho-García, A. M. López-Pérez, N. Bilbao, S. Romero-Pérez, M. J. Mayoral, D. González-Rodríguez, Angew. Chem. Int. Ed. 2015, 54, 6780-6784. [3] M. J. Mayoral, N. Bilbao, D. González-Rodríguez, ChemistryOpen, 2016, 5, 10-32. [4] C. Montoro-García, J. Camacho-García, A. M. López-Pérez, M. J. Mayoral, N. Bilbao, D. GonzálezRodríguez, Angew. Chem. Int. Ed. 2016, 55, 223-227. [5] N. Bilbao, I. Destoop, S. De Feyter, D. González-Rodríguez, Angew. Chem. Int. Ed. 2016, 55, 659-663. [6] C. Montoro-García, M. J. Mayoral, R. Chamorro, D. González-Rodríguez, Angew. Chem., Int. Ed. 2017, 56, 15649- 15653.
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Symposium on Foldamers Bordeaux 2018 Poster P7
Peptide Foldamers in Drug Discovery
Yosuke Demizu,a Takashi Misawa,a Genichiro Tsujia
aDivison of Organic Chemistry, National Institute of Health Sciences, Japan [email protected]
Helices in proteins are most abundant and important secondary structures that recognize macromolecules such as other proteins and DNA, and play an important role in a variety of fields such as biology, medicinal chemistry, and organic chemistry. Therefore, peptide-based helical foldamers have been developed in recent years. As tools for peptide-helix stabilization, non- proteinogenic amino acids such as ,-disubstituted -amino acids, cyclic -amino acids, and cross- linked side chains are often utilized. Herein we present secondary structural control of short peptides using the above non-proteinogenic amino acids.[1],[2] Furthermore, we applied the stabilized helical peptides to the inhibitors of nuclear receptor (ER, VDR)-coactivator interaction,[3],[4] to the protein-degradation inducers,[5] to the antimicrobial peptides,[6] and to the efficient cell-penetrating molecules (Figure 1).[7],[8],[9]
Figure 1. Illustrative image of peptide foldamers in drug discovery.
References [1] H. Kobayashi, T. Misawa, K. Matsuno, Y. Demizu,* J. Org. Chem. 2017, 82, 10722-10726. [2] T. Misawa,* Y. Kanda, Y. Demizu,* Bioconj. Chem. 2017, 28, 3029-3035. [3] T. Misawa, Y. Demizu,* M. Kurihara,* et al., Bioorg. Med. Chem. 2015, 23, 1055-1061. [4] T. Nagakubo, Y. Demizu*, M. Kurihara,* et al., Bioconj. Chem. 2014, 25, 1921-1924. [5] N. Ohoka, T. Misawa, M. Kurihara, Y. Demizu,* M. Naito,* Bioorg. Med. Chem. Lett. 2017, 27, 4985-4988. [6] T. Misawa, Y. Kikuchi,* Y. Demizu,* et al., Bioorg. Med. Chem. Lett. 2017, 27, 3950-3953. [7] H. Yamashita, Kurihara,* Y. Demizu,* et al., Sci. Rep. 2016, 6, 33003. [8] H. Yamashita, Kurihara,* Y. Demizu,* et al., ChemBioChem 2016, 17, 137-140. [9] Y. Demizu,* S. H. Gellman, et al., Org. Biomol. Chem. 2015, 13, 5617-5620.
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Symposium on Foldamers Bordeaux 2018 Poster P8
Templating Complex De Novo Proteins with Miniprotein Motifs
Debbie Nicol,a Emily G. Baker,a Christopher W. Wood,a Kathryn L. Porter Goff,a Matthew P. Crump,a,b and Derek N. Woolfson a,b,c aSchool of Chemistry, University of Bristol, Cantock’s Close, BS8 1TS, UK bBrisSynBio, University of Bristol, Life Sciences Building, Tyndall Avenue, Bristol, BS8 1TQ, UK cSchool of Biochemistry, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, BS8 1TD, UK [email protected]
Recently, we used a fragment-based design approach to create a new miniprotein, PP, which comprises a polyproline-II helix-turn- helix topology and forms a compact folded unit (Figure 1).[1] An optimized PP was achieved through rational redesign towards a de novo framework.[2] oPP is monomeric and highly thermally stable for its small size.
Figure 1. The PP miniprotein.[1]
The PP motif is now being used as a template for the construction of more complex de novo proteins. New PP-based proteins are being parameterized in silico using ISAMBARD, our in-house biomolecular model building and analysis software.[3] Biophysical characterizations of initial trimeric designs are promising. Ultimately, we aim to furnish our new PP-derived proteins with function.
References [1] E. G. Baker, C. Williams, K. L. Hudson, G. J. Bartlett, J. W. Heal, K. L. Porter Goff, R. B. Sessions, M. P. Crump, D. N. Woolfson, Nat. Chem. Biol., 2017, 13, 764-770. [2] K. L. Porter Goff, D. N. Woolfson, unpublished work. [3] C. W. Wood, J. W. Heal, A. R. Thomson, G. J. Bartlett, A. Á. Ibarra, R. L. Brady, R. B. Sessions, D. N. Woolfson, Bioinformatics, 2017, 33, 3043-3050.
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Symposium on Foldamers Bordeaux 2018 Poster P9
Helical aromatic oligoamide foldamers for protein surface recognition: an anchoring approach
Saireddy Post,a,b Lucile Fischer,a,b Béatrice Langlois d’Estaintot,b Thierry Granier ,b Cameron Mackereth,a,c Ivan Huc.a,b,d
a Univ. Bordeaux, CNRS, Institut Européen de Chimie et Biologie, Pessac, France; b UMR 5248, CBMN; c ARNA (U 1212), INSERM; d Department of Pharmacy, Ludwig-Maximilians-Universität, München, Germany. [email protected]
Many biological processes are driven by protein-protein interactions (PPIs) which thus represent potential targets to develop new therapeutic approaches.[1] The recognition of protein surface features by smaller molecules is a means to mask and inhibit these PPIs. In particular oligoamide quinoline based helical foldamers[2a] developed in our team may cover large surface areas. They exist as a racemic mixture of right-handed (P) and left-handed (M) helices. Our hypothesis is that interactions between such a foldamer and a protein surface will result in a helix sense bias in favor of one handedness over the other. We chose this read out for our screening method by looking at the induced circular dichroism (ICD) signal resulting from a preferred handedness.[2b, 2c] In order to enhance possible interactions between the foldamers and the protein surface, we proposed to increase the length of foldamers while keeping ICD as a read out method. For long- foldamers, we introduced more flexible aminomethyl pyridine units (P monomer) and made QP hybrid foldamers and finally tested them for protein surface recognition by inhibitor approach on a model protein: the human carbonic anhydrase II (HCAII). Foldamers with up to 14 units were shown to interact with HCA and several foldamer-HCA complexes were characterized by x-ray crystallography. In another study, a tethering approach was developed to detect interactions between a protein and a foldamer. Cysteine mutants of therapeutically relevant proteins (CypA and IL4) were produced. Series of foldamers were synthesized bearing different proteinogenic side chains and linker functionalized with an active disulfide. Foldamers from 4 to 14 units were shown to interact with the protein surfaces and several foldamer-protein complexes were characterized by solution NMR and x- ray crystallography. These cases constitute valid candidates for structural elucidation of the interactions involved.
Figure 1. Anchoring approaches used to elucidate interactions between aromatic oligoamide foldamers and protein surfaces
References [1] L.-G. Milroy, T. N. Grossmann, S. Hennig, L. Brunsveld, C. Ottmann, Chem. Rev. 2014, 114, 4695-4748. [2] (a) G. Guichard, I. Huc, Chem. Commun. 2011, 47, 5933-5941. (b) J. Buratto, C. Colombo, M. Stupfel, S. J. Dawson, C. Dolain, B. Langlois d’Estaintot, L. Fischer, T. Granier, M. Laguerre, B. Gallois, I. Huc, Angew. Chem., Int. Ed. 2014, 53, 883-887. (c) M. Jewginski, T. Granier, B. Langlois d’Estaintot, L. Fischer, C. D. Mackereth, I. Huc, J. Am. Chem. Soc. 2017, 139, 2928-2931.
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Symposium on Foldamers Bordeaux 2018 Poster P10
Synthesis of 6-substituted quinoline foldamer building blocks
Márton Zwillinger,a,b Márton Csékei,b András Kotschyb
a Eötvös Loránd University, Pázmány Péter stny. 1/a, Budapest 1117, Hungary, b Servier Research Institute of Medicinal Chemistry, Záhony utca 7, Budapest 1031, Hungary [email protected] [email protected] [email protected]
Synthesis and properties of foldamers based on 8-amino-2-quinolinecarboxylic acid building blocks bearing various sidechains in the positions 4 or 5 has been thoroughly studied in the last decade. Controlling several properties of the oligomers through the quality of their sidechains have been reported. [1-7] However consequences deriving from different substitution patterns of the quinoline core have not been fully explored. We hypothesized that application of 6-substituted 8- amino-2-quinolinecarboxylic acid building blocks in foldamer synthesis might lead to the displacement of sidechains on the helix surface thus resulting in modified properties of oligomers. Herein we report the synthesis of quinoline based foldamer building blocks bearing proteinogenic sidechains attached to position 6 via various length aliphatic linkers. The Fmoc protected main chain amine and acid-labile protections of the side chains (N-Boc, O-tBu) are designed to be compatible with solid phase synthesis. The presented work involves the large scale synthesis of an advanced late-stage intermediate, preparation of the desired building blocks by late-stage functionalization and preliminary experiments assessing the cleavability of sidechain protecting groups. The gram scale syntheses established a route to 6-substituted building blocks opening the doors to solid phase syntheses and study of oligomers.
Figure 1. General structure of 6-substituted aromatic oligoamide foldamer building blocks
References [1] E. R. Gillies, C. Dolain, J. M. Leger, I. Huc, The Journal of organic chemistry 2006, 71, 7931-7939. [2] E. R. Gillies, F. Deiss, C. Staedel, J. M. Schmitter, I. Huc, Angewandte Chemie 2007, 46, 4081-4084. [3] S. J. Dawson, Á. Mészáros, L. Pethő, C. Colombo, M. Csékei, A. Kotschy, I. Huc, European Journal of Organic Chemistry 2014, 2014, 4265-4275. [4] S. J. Dawson, X. Hu, S. Claerhout, I. Huc, Methods in enzymology 2016, 580, 279-301. [5] C. Tsiamantas, S. J. Dawson, I. Huc, Comptes Rendus Chimie 2016, 19, 132-142. [6] X. Hu, S. J. Dawson, P. K. Mandal, X. de Hatten, B. Baptiste, I. Huc, Chemical science 2017, 8, 3741-3749. [7] Z. Liu, X. Hu, A. M. Abramyan, A. Mészáros, M. Csékei, A. Kotschy, I. Huc, V. Pophristic, Chemistry-A European Journal 2017, 23, 3605-3615.
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Symposium on Foldamers Bordeaux 2018 Poster P11
β-Barrel construction by metal-directed folding and assembly
Motoya Yamagami,a Tomohisa Sawada,a Makoto Fujitaa,b
aDepartment of Applied Chemistry, School of Engineering, The University of Tokyo, bInstitute for Molecular Science [email protected]
The chemical construction of a β-barrel structure, one of the important protein tertiary structures possessing internal pores surrounded by curved β-sheets, have attracted a lot of biologist and chemists. However, the synthesis of precise β-barrel structures has limited to a few examples[1,2] due to the strong tendency of β-sheet peptides to aggregate into insoluble fibers. In this work, we succeeded in the de novo synthesis of a β-barrel structure with a pore by the metal-directed folding and assembly of a short peptide fragment.[3] Octapeptide 1, which has the FVFVXPGP sequence [where X = 3-aminobenzoic acid] and pyridyl groups at both N- and C-termini, was designed and synthesized by solution-phase peptide synthesis. The complexation of 1 and ZnI2 afforded single crystals without the precipitation of β-sheet aggregates. The X-ray diffraction study revealed the formation of (1)2(ZnI2)2 macrocyclic antiparallel β-sheets, where the FVFV sequence was folded into β-sheet conformation and linked by the loop conformation of the PGP sequence. This macrocycles further assembled into the trimer (2), which was the synthetic β-barrel composed of six β-strands with the shear number of 12. Inside β-barrel 2, a 30 Å2-sized pore was confirmed, in which all the Val residues were precisely accumulated. Thus, we succeeded in construction of the precise β-barrel with an internal pore.
- F - V - F - V - - P - G - P -
H O H O H O O H N N N N N N N N N N N O H O H O H O O
1 =
ZnI2 =
folding & assembly
3 2 (1)2(ZnI2)2 macrocycle
Figure 1. Ligand design of 1 and its folding and assembly into synthetic β-barrel 2.
References [1] C. Liu, M. Zhao, L. Jiang, P.-N. Cheng, J. Park, M. R. Sawaya, A. Pensalfini, D. Gou, A. J. Berk, C. G. Glabe, J. Nowick, D. Eisenberg, Proc. Natl. Acad. Sci. USA 2012, 109, 20913–20918. [2] A. Laganowsky, C. Liu, M. R. Sawaya, J. P. Whitelegge, J. Park, M. Zhao, A. Pensalfini, A. B. Soriaga, M. Landau, P. K. Teng, D. Cascio, C. Glabe, D. Eisenberg, Science 2012, 335, 1228–1231. [3] Manuscript submitted.
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Symposium on Foldamers Bordeaux 2018 Poster P12
Peptidic Cu+-Responsive Luminescent Probes Inspired by the Copper Chaperone CusF
A. Roux,a M. Isaac,a V. Chabert,a S. A. Denisov,b N. D. McClenaghanb and O. Sénèquea
aUniv. Grenoble Alpes, CNRS, CEA, BIG, LCBM (UMR 5249), 38000 Grenoble, France, bUniv. Bordeaux, CNRS, ISM (UMR 5255), 33405 Talence, France nathan.mcclenaghan@ u-bordeaux.fr
Copper(I) is a soft metal ion that plays an essential role in living organisms and Cu+-responsive probes are required to detect Cu+ ions in physiological conditions and understand its homeostasis as well as the diseases associated with its misregulation. Herin, we describe a series of cyclic peptides, which are structurally related to the copper chaperone CusF, and that behave as Cu+-repsonsive probes. These peptide probes comprise the 16-amino acid loop of CusF cyclized by a -turn inducer dipeptide and functionalized by a Tb3+ complex for its luminescence properties. The mechanism of luminescence enhancement relies on the modulation of the antenna effect between a tryptophan residue and the Tb3+ ion within the probe when Cu+ forms a cation- interaction with tryptophan, as revealed by steady-state and time-resolved spectroscopies. Here, we further investigate the influence of the amino acid sequence of these cyclic peptides on the copper-induced modulation of Tb3+ emission and show that the rigid -turn inducer Aib-D-Pro and insertion of the Tb3+ complex close to its tryptophan antenna are required to obtain turn-on Cu+ responsive probes. We also show that the amino acid sequence, especially the number and position of proline residues has a significant impact on metal-induced luminescence enhancement and metal-binding constant of the probes.[1], [2]
Figure 1. A bio-inspired Cu+-responsive luminescent probe.[1], [2]
References [1] M. Isaac, S. A. Denisov, A. Roux, D. Imbert, G. Jonusauskas, N. D. McClenaghan, O. Sénèque, Angew. Chem. Int. Ed. 2015, 54, 11453. [2] A. Roux, M. Isaac, V. Chabert, S. A. Denisov, N. D. McClenaghan, O. Sénèque, Org. & Biomol. Chem., 2018, in press.
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Symposium on Foldamers Bordeaux 2018 Poster P13 Foldamer-based Structural and Functional Analysis of Amyloid Proteins
Sunil Kumara, Anja Henning-Knechtelb, Mazin Magzoubb, and Andrew D. Hamiltona
aDepartment of Chemistry, New York University, bBiology Program, New York University Abu Dhabi [email protected]
The prevailing hypothesis stipulates that the pre-amyloid oligomers of Aβ are the main culprits associated with the onset and progression of Alzheimer’s disease (AD), which has prompted efforts to search for therapeutic agents with the ability to inhibit Aβ oligomerization and amyloidogenesis.1,2 However, the lack of clinical progress is impeded by the limited structural information about the neurotoxic oligomers. To address this issue, we have adopted a synthetic approach, where a library of oligopyridylamide-based small molecules was tested against various microscopic events implicated in the self-assembly of Aβ. Foldamers have been shown to modulate the structure and functions of intrinsically disordered proteins.3-14 Two oligopyridylamides bind to different domains of Aβ and affect distinct microscopic events in Aβ self-assembly. The study lays the foundations for a dual recognition strategy to simultaneously target different domains of Aβ for further improvement in anti-amyloidogenic activity. The data demonstrate that one of the most effective oligopyridylamides forms a high affinity complex with Aβ, which sustains the compound’s activity in cellular milieu. The oligopyridylamide was able to rescue cells when introduced 24 h after the incubation of Aβ. The synthetic tools utilized here provide a straightforward strategic framework to identify a range of potent antagonists of Aβ-mediated toxic functions. This approach could be a powerful route to the design of candidate drugs for various amyloid diseases which have so far proven to be ‘untargetable'.
Figure 1. Kinetic pathways of Aβ fibrillation in the absence and presence of foldamer based ligands.
References 1. Chiti F. et al. Annu. Rev. Biochem. 2006, 75, 333-366. 2. Selkoe D. J. Nature 2003, 426, 900-904. 3. Kumar S. et al. J. Am. Chem. Soc. 2018, 140, 6562-6574. 4. Birol M., Kumar S. et al. Nature Commun. 2018, 9, 1312, 1-12. 5. Kumar S. et al. Org. Biomol. Chem. 2018, 16, 733-741. 6. Kumar S. et al. J. Am. Chem. Soc. 2017, 139, 17098-17108. 7. Kumar S. and Hamilton A.D. J. Am. Chem. Soc. 2017, 139, 5744−5755. 8. Kumar S. and Hamilton A.D. Patent 2017. 9. Miranker A.D. and Kumar S. Patent 2016. 10. Kumar S. et al. Nature Commun. 2016, 7, 11412, 1-11. 11. Kumar S. et al. Chem. Comm. 2016, 52, 6391-6394. 12. Kumar S. et al. Chem. Biol. 2015, 22, 369-378. 13. Kumar S. et al. Chem. Biol. 2014, 21, 775-781. 14. Kumar S. Miranker A.D. Chem. Comm. 2013, 49, 4749-4751.
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Symposium on Foldamers Bordeaux 2018 Poster P14
Finding allosteric hot-spots on RecQ helicase through -peptide foldameric fragment library screening
Attila Tököli,a Éva Bartus b, Matam Losery Stanley Paul a, Gerda Szakonyi a, Anasztázia Hetényi b, Tamás Martinek b
aUniversity of Szeged, Faculty of Pharmacy, Institute of Pharmaceutical Analysis ,bUniversity of Szeged, Faculty of Medicine, Institute of Medicinal Chemistry [email protected]
The increasing appearance of multidrug resistant bacteria is becoming an urgent problem. Most of the clinically relevant antibiotics are small molecular enzyme inhibitors of which development is less appealing for pharma companies. Inhibiting bacterial protein-protein interactions (PPI) however may provide new tools against resistant strains. Interaction between the procaryotic proteins RecQ helicase Winged Helix domain (WH domain) and Single-stranded DNA-binding protein (SSB) was chosen as model PPI. Disrupting this interaction has been found to inhibit bacterial growth. [1] The binding hot- spot of SSB-C-terminal octapeptide on WH domain was previously determined using NMR experiments by Shereda et. al. [2] Our goal, is to improve affinity and selectivity of SSB-Ct peptide by extending its interactions to two hot-spots. PPI hotspots of WH domain was mapped using a foldameric fragment library pull-down assay method developed in our lab.[3] Our -peptide library consisted of hexameric H14 (trans-1,2- aminocyclohexane acid) helices, projecting two proteogenic side chains on the same face, using 16 different 3-amino acid in both position (pos 2 and pos 5) yielding a 256-membered fragment library. [3] RecQ-WH protein was cloned and expressed using conditions determined by Shereda et. al.[2] The best binding fragments captured by the pull-down assay were further investigated via HSQC NMR-titration experiments. One fragment, containing 3-tryptophan in both positions was found to bind to an allosteric binding site alongside with the SSB-Ct peptide. To further analyse this interaction, in silico simulations were used to assist the determination of the orientation of the bound fragments. These findings will enable us to develop a high-affinity protein-protein interaction inhibitor for the RecQ-WH-SSB-Ct complex.
Figure 1. Amino acids affected by SSB-Ct (green), H14WW (blue) binding to RecQ-WH protein determined by HSQC NMR-titration. Yellow shows amino acids affected by both ligands.
References [1] Amiee. H. Marceau, Douglas A. Bernstein, James L. Keck, 2013, PLoS ONE 8(3): e58765. [2] Shereda R. D, Reiter N. J., Butcher S. E., Keck J. L, 2009, Journal of Molecular Biology, 386, 612–625 [3] Bartus É, Hegedűs Z, Martinek TA, 2017, ChemistryOpen, 6(2):236-241
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Symposium on Foldamers Bordeaux 2018 Poster P15
A self-assembled double helical aromatic oligoamide capsule for the simultaneous encapsulation of xylose and arabinose
Pedro Mateus,a,b Nagula Chandramouli,a,b Cameron Mackereth,a,c Brice Kauffmann,a,d Yann Ferrand,a,b Ivan Huc.a,b,e
a Univ. Bordeaux, CNRS, Institut Européen de Chimie et Biologie, Pessac, France;b UMR 5248, CBMN; c ARNA (U 1212), INSERM; d UMS3033/US001, INSERM; e Department für Pharmazie, Ludwig-Maximilians-Universität, München, Germany. [email protected]
Helically folded capsules based on aromatic oligoamides are a class of molecular containers that can completely enclose substrates, isolating them from the outside medium.[1] Their reduced diameter at each extremity and wider diameter at the centre defines cavities in which the helix inner wall is decorated with numerous hydrogen bond donors and acceptors. These have been shown to promote tight, selective, and diastereoselective binding of monosaccharides,[2] arguably one of the most challenging targets for molecular recognition. Recent efforts in our group have focused on targeting larger and more complex guest molecules. Although this can be achieved by increasing the number of monomers that code for larger cavities, as a different approach, self-assembly can rapidly produce large and symmetrical supramolecular containers with cavities that can also host guest molecules using lesser number of building blocks and requiring less synthetic effort.[3] Herein we introduce an aromatic oligoamide strand that is shown to fold and self-assemble into a double helical capsule possessing a sizeable polar cavity in its centre (Fig. 1). Solution and solid-state studies showed that the cavity is large enough to accommodate two monosaccharide guests. More importantly, results showed that the double helical capsule can form an heterocomplex 4 1 by simultaneously binding α- C1-D-xylopyranose and - C4-D-arabinopyranose.
Figure 1. X-ray crystal structures evidencing self-assembly of a small oligomeric strand into a double helical capsule, as well as encapsulation of two different monosaccharide guests.
References [1] C. Bao, B. Kauffmann, Q. Gan, K. Srinivas, H. Jiang, I. Huc, Angew. Chem. Int. Ed. 2008, 47, 4153. [2] N. Chandramouli, Y. Ferrand, G. Lautrette, B. Kauffmann, C. D. Mackereth, M. Laguerre, D. Dubreuil, I. Huc, Nature Chemistry 2015, 7, 334. [3] N. Chandramouli, Y. Ferrand, B. Kauffmann, I. Huc, Chem.Commun. 2016, 52, 3939.
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Symposium on Foldamers Bordeaux 2018 Poster P16
Highly tunable slide-ring gels
Jérémie Bourotte, Charles-André Fustin, Michael Singleton *
Université Catholique de Louvain, Institute for Condensed Matter and Nanosciences – Molecules, Solids, and Reactivity Division; Laboratory for Supramolecular and Biomimetic Reactivity [email protected]
Slide-ring gels are a relatively new class of polymer network of interest from both a fundamental stand point and for numerous applications. In these gels, the polymer stands are held together by linked macrocycles (rings) with each ring having a polymer chain threaded through its cavity to give rotaxane structures. This generates cross-links that can move (slide) resulting in unique mechanical properties. The majority of slide-ring gels are based on rotaxanes using connected cyclodextrins as the macrocycles and PEG as the polymer. This presents some limitations in the ability to readily modify the properties of these systems and as a result to test or better understand the factors contributing to their unique properties. [1-2] The recent description of foldaxanes by Huc and co-workers opens up a new possibility in the design of slide-ring gels; the use of pseudo-macrocyclic structures based on well-folded oligomers. [3-4] Our approach to the development of new slide-ring gels is through the use of short aromatic oligoamide foldamer (AOF) sequences designed to have a high-affinity for urea or carbamate groups in a polymer strand. To best optimize the interactions between the foldamer and the polymer, a series of short AOF sequences have been synthesized and their affinity for linear carbamates/urea containing molecules has been studied by NMR. The results of these studies and the perspectives of this approach are described.
b) a) c)
Figure 1. a) Schema – taken from [3] – and AOF receptor structure b) Slide-ring gel by the AOF approach c) Schema of interactions with (X = NH) urea or (X = O) carbamate as strand.
References [1] Y. Okumura, K. Ito, Adv. Mater. 2001, 13, 485-487 [2] S. Granick, M. Rubinstein, Nature Materials 2004, 3, 586-587 [3] Q. Gan, Y. Ferrand, C. Bao, B. Kauffmann, A. Grélard, H. Jiang, I. Huc, Science 2011, 331, 1172-1175 [4] X. Wang, B. Wicher, Y. Ferrand, I. Huc, J. Am. Chem. Soc. 2017, 139, 9350-9359
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Symposium on Foldamers Bordeaux 2018 Poster P17
Helical dynamic architectures based on functionalized foldamers
Lara Faour,a Fatima Aparicio,a Magali Allain,a David Canevet, a Marc Salléa
aMOLTECH-Anjou Laboratory, University of Angers, France [email protected]
Foldamers constitute an interesting class of oligomers that can fold into conformationally ordered architectures.[1] Such compact conformations show structural and functional similarities with biopolymers, mimicking their well-organized structures and functions, and explaining the intensively growing interest regarding their supramolecular chemistry. A wide variety of building blocks (e.g. peptides, ureas…) have been reported to form foldameric structures through weak intramolecular interactions and have displayed remarkable properties in the context of chiral materials, molecular recognition or catalysis, for instance. While important efforts have been devoted to the study of these dynamic structures and their stimuli-controllable conformational changes, pi-functional helical foldamers remain scarce in the literature. On this ground, we have recently depicted the synthesis of photoactive and electro-switchable foldamers endowed with push-pull chromophores or redox units, designed to afford dynamic, and hence stimuli-responsive architectures with appealing optical and electronic properties.[2] They involve an oligoamide-based skeleton, a relevant choice given the predictability and the stability of the corresponding folded structures as well as their straightforward synthetic access, which allowed grafting different conjugated systems.
Figure 1. X-Ray crystal structure of an oligopyridine-dicarboxamide foldamer endowed with photoactive Disperse-Red 1 units.
References [1] G. Guichard, I. Huc, Chemical Communications 2011, 47, 5933. [2] F. Aparicio, L. Faour, M. Allain, D. Canevet and M. Salle, Chemical Communications 2017, 53, 12028.
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Symposium on Foldamers Bordeaux 2018 Poster P18
Triazolium-based cationic amphipathic peptoid oligomers
Radhe Shyam,a Cassandra Perez,a Nicolas Charbonnel,b Christelle Blavignac,c Olivier Roy, a Christiane Forestier,b Claude Taillefumiera and Sophie Faurea
a Université Clermont Auvergne, CNRS, SIGMA Clermont, ICCF, F-63000 Clermont-Ferrand, France, b Université Clermont Auvergne, CNRS, LMGE, F-63000 Clermont-Ferrand, France, c Université Clermont Auvergne, Centre Imagerie Cellulaire Santé, F-63000 Clermont-Ferrand, France [email protected]
Synthetic oligoamides exhibiting the mechanism of action of natural antimicrobial peptides (AMPs) with enhanced proteolytic stability have been widely explored during the last decade. Many of these mimics have been designed to adopt cationic amphipathic helical structure of native AMPs, which is the key determinant of their activity.[1] Among them, peptoids (N-substituted glycine oligomers) represent a promising class of AMP mimics.[2] Peptoids are inherently more flexible than peptides due to the absence of internal hydrogen bonding and the presence of N,N-disubstituted amides which can populate both cis and trans conformations. However peptoids still retain propensities to adopt stable helical secondary structures provided the cis/trans isomerism is optimally controlled.[3] In this communication, we will present the potential of the triazolium group as a cationic moiety and helix inducer[4] to develop potent and selective antimicrobial peptoids.
Figure 1. a) Generic structure of triazole- and triazolium-based amphipathic peptoid oligomers, b) Circular dichroism curve of a peptoid hexamer and SEM micrograph of S. Aureus cells treated with a cationic amphipathic oligomer.
References [1] B. Findlay, G. G. Zhanel, F. Schweizer, Antimicrob. Agents Chemother. 2010, 54, 4049. [2] N. P. Chongsiriwatana, J. A. Patch, A. M. Czyzewski, M. T. Dohm, , A. Ivankin, D. Gidalevitz, R. N. Zuckermann, A. E. Barron, Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 2794. [3] O. Roy, G. Dumonteil, S. Faure, L. Jouffret, A. Kriznik, C. Taillefumier, J. Am. Chem. Soc. 2017, 139, 13533. [4] C. Caumes, O. Roy, S. Faure, C. Taillefumier, J. Am. Chem. Soc. 2012, 134, 9553.
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Symposium on Foldamers Bordeaux 2018 Poster P19
Enamine catalysis using thiazole-based γ-peptide foldamers
Julie Aguesseaua, Renata Marcia de Figueiredob, Jean-Marc Campagneb, Baptiste Legranda, Ludovic Maillarda
aInstitut des Biomolécules Max Mousseron, UMR 5247 CNRS-ENSCM-UM, UFR de Pharmacie, Montpellier, France. bInstitut Charles Gerhardt UMR 5253 ENSCM-ICGM-CNRS-UM, ENSCM Montpellier, France [email protected]
We have recently described a class of constrained heterocyclic γ-amino acids built around thiazole ring named ATCs.[1] In this study, the high propensity of ATC oligomers to adopt a helical structure in both organic solvents and water was demonstrated.[2] Moreover, the highly robust synthetic pathway guarantees a widely divers access to enantiopure ATCs, permitting to modulate the lateral chains decorating the oligomer scaffold.[3] Although, foldamers have been explored for material and biomedical applications, their potential as asymmetric catalyst has not been investigated much.
We report herein our efforts to design and synthesize ATC-based helical foldamers as tunable organo-catalysts. Investigating known reaction manifolds will enable to benchmark the effectiveness of folded ATC oligomers against small molecule catalysts. Hence, the primary focus is on the enamine-catalytic Michael addition reaction as it potentially presents one of the most effective ways for asymmetric carbon-carbon bond-formation. After the identification of an ATC-building block with catalytic properties has been performed, the impacts of the foldamer microenvironment on both the catalytic activity and the chirality transfer is being researched.
Figure 1. Nitro-Michael addition reaction catalysed by ATC based foldamers
References [1] L. Mathieu, B. Legrand, C. Deng, L. Vezenkov, E. Wenger, C. Didierjean, M. Amblard, M.-C. Averlant-Petit, N. Masurier, V. Lisowski, J. Martinez, L. T. Maillard, Angew. Chem. Int. Ed. Engl. 2013, 52, 6006 [2] C. Bonnel, B. Legrand, J.-L. Bantignies, H. Petitjean, J. Martinez, N. Masurier, L. T. Maillard, Org. Biomol. Chem. 2016, 14, 8664 [3] L. Mathieu, C. Bonnel, N. Masurier, L. T. Maillard, J. Martinez, V. Lisowski, Eur. J. Org. Chem. 2015, 10, 2262
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Symposium on Foldamers Bordeaux 2018 Poster P20
Foldamers as a tool for introducing hydrogen bond networks into the second coordination sphere around iron bounds thiolates
Oscar Bautista-Aguilera and Michael Singleton
Institute of Condensed Matter and Nanosciences, UCL, Louvain-la-Neuve, Belgium. [email protected]
Iron-sulphur or iron-thiolate metal sites in biological systems play essential roles in electron transport, the activation of small molecules including H2, O2, N2, etc. Nevertheless, their reactivity is strongly influenced by the surrounding protein environment and the essential SCS interactions that control the reactivity are not well-understood [1]. Particularly, in enzymes such as superoxide dismutases or reductases, where hydrogen peroxide is produced, the ability to control or prevent oxidation of metal-thiolates is likely controlled by the SCS. While synthetic systems have shown that hydrogen-bonding interactions with substrates (oxygen species) can stabilize these species and prevent side reactions, little attention has been paid to the extent to which sulphur oxidation can be inhibited through the presence of hydrogen bonds with the second coordination sphere.
Developing synthetic systems where specifically placed hydrogen bonds can be incorporated around metal thiolates could provide significant insight into the above processes. Our group uses aromatic oligoamide foldamers,[2] which are synthetic molecules that adopt stable secondary structures in solution, to design the microenvironments around metal complexes. By using this approach with a model iron-bound thiolate complex, we can specifically include a hydrogen bonding network around the thiolate. Moreover, by introducing competing groups for the hydrogen bonds we should be able to control the hydrogen bonding strength as well. By studying the changes in electronic properties and reactivity of the metal site, with the changes in the ligand structure and included non-covalent interactions, a better understanding of the structure function relationships resulting from second coordination sphere hydrogen bonding networks can be obtained.
Figure 1. A) Synthetic targets for studying the effect of hydrogen bonding strength on iron bound thioloates.
References [1] Willar-Acevedo. G, et al, J. Am. Chem. Soc. 2017, 139, 119. [2] Zhang. D, et al, Chem. Rev. 2012, 112, 5271.
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Symposium on Foldamers Bordeaux 2018 Poster P21
Design of Abiotic Foldamer Tertiary Structures
Daniela Mazzier,a Soumen De,b Thierry Granier,b Victor Maurizot,b Ivan Huca
aDepartment of Pharmacy, Ludwig-Maximilians-Universität, Munich, Germany, bUniversité de Bordeaux, CNRS, CBMN (UMR5248), Institut Européen de Chimie et Biologie, Pessac, France. [email protected]
Over the last decades, numerous non-natural foldamer backbones have been developed for the construction of original, predictable, and well defined molecular architectures.[1] The research was mainly focused on the design of structures analogous to secondary motifs of biopolymers, such as helices, sheets and turns.[2] However, most of the functions of biopolymers, especially of proteins, emerge at the level of their tertiary structures and would not be achieved by an isolated α-helix or β- sheet. Thus, the design of artificial tertiary folds that comprise several secondary structural elements represents a major challenge.
Tertiary folds based on non-natural monomers remain an unexplored area and may give access to shapes and functions different to those of peptides and nucleotides. Due to the stability and the predictability of their folded secondary structures, aromatic oligoamide foldamers possess a high potential in the field of peptidomimetics.[3] Therefore, the high stability of aromatic amide helices can be exploited to create complex artificial tertiary structures.
In this context, we focused our attention on the design, the synthesis and the characterization of oligoamide-quinoline foldamers that have side chains designed to interact with each other to form helix-turn-helix motifs.[4] Moreover, the possibility to increase the complexity of our systems and to accommodate the presence of more flexible backbone features are currently under investigation.
Figure 1. Design of helix-turn-helix motif from primary sequence to tertiary structure.
References [1] J. Guichard, I. Huc Chem. Commun. 2011, 47, 5933. [2] R. V. Nair, K. N. Vijayadas, A. Roy, G. J. Sanjayan Eur. J. Org. Chem. 2014, 2014, 7763. [3] I. Huc Eur. J. Org. Chem. 2004, 17. [4] S. De, B. Chi, T. Granier, T. Qi, V. Maurizot, I. Huc Nat. Chem. 2018, 10, 51.
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Symposium on Foldamers Bordeaux 2018 Poster P22
Towards the Design and Synthesis of Multi-Stranded β-sheets foldamers.
Camille Perdriau,a Christel Dolain,a Brice Kauffmann,b Gilles Guichard
a Université de Bordeaux, CNRS, CBMN UMR 5248, IECB, Pessac, France.b Université de Bordeaux, CNRS, UMS 3033, IECB, Pessac, France. [email protected]
Functions fulfilled by proteins (catalysis, transport, molecular recognition etc.) are directly dependent on their three-dimensional structures, that is the reason why numerous researchers have been inspired by those biopolymers to design artificial architectures with a well-defined folding ability, called Foldamers.[1] In order to enrich the register of protein secondary structures accessible to foldamers, it seems judicious to develop artificial architectures mimicking the folding of protein β-sheets.[2] Indeed, the helix is by far the most frequently reported type of secondary structure among foldamers and there are comparatively much less examples of foldamers forming sheet-like structures. [3] The scarcity of foldamer-based sheet like architectures may be due to their greater tendency to aggregate and precipitate when isolated, and to the need for stabilization within a tertiary fold to remain in solution. Here we present a rational approach for the construction of synthetic multi-stranded β-sheets. Our strategy relies on the formation of intramolecular hydrogen bonds in oligomers composed of alternating diamines and diacid units. Short diamine and diacid strands are connected by an hairpin turn, named D-Pro-DADME, that would set the linear strands at a distance and orientation allowing β-sheet formation.[4] Different parameters were taken into account to design various peptidomimetics such as their strands’ length and rigidity. Indeed, convergent multi-step synthesis in solution was elaborated to access 2-, 3- and 5-stranded molecules containing both urea and amide junctions. Furthermore, conformational studies were performed in solution and in the solid state to check whether compact folded structures were obtained.
Figure 1. a) D-Pro-DADME turn used in artificial β-sheets. b) Schematic representation of the protein β-sheet folding for a 3-stranded molecule (left) and a 5-stranded molecule (right) and their hydrogen bonding patterns (dotted line).
References [1] S.H. Gellman, Acc. Chem. Res.,1998, 31, 173-180. [2] O. Khakshoor, J.S. Nowick, Curr. Opin. Chem. Biol. 2008, 12, 722–72. [3] R. Spencer, K.H. Chen, G. Manuel, J.S. Nowick, Eur. J. Org. Chem., 2013, 3523–3528. [4] J.D. Fisk, D.R. Powell, S.H. Gellman, J. Am. Chem. Soc. 2000, 122, 5443-5447.
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Symposium on Foldamers Bordeaux 2018 Poster P23
Development of pyridine–acetylene–aniline oligomers as a new architecture of helical receptors against saccharides
Yuki Ohishi, Masahiko Inouye
Graduate School of Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan [email protected]
We have developed pyridine–acetylene–phenol oligomers as helical receptors for saccharides (Figure 1).[1] These oligomers strongly associate with saccharides by hydrogen-bonding in a push- pull fashion, where the nitrogen atoms of the pyridine rings and the hydroxy groups of the phenol rings work as a hydrogen-bonding acceptor and donor, respectively. Here, we newly designed and synthesized two types of pyridine–acetylene–aniline oligomer 1 and 2, in which aniline rings possess alkyl and amido side chains at the 4-positions, respectively. Because amino groups of the aniline rings can work as a hydrogen-bonding donor, these oligomers were also expected to associate with saccharides in a push-pull fashion. Pyridine–acetylene–aniline oligomers 1 and 2 were synthesized by the Sonogashira reactions repeatedly. In 1,2-dichloroethane solutions, these oligomers associated with octyl -D- glucopyranoside (-Glc) to show induced circular-dichroism bands. The association constant of 2 (Ka 6 −1 5 −1 ≈ 1 × 10 M ) with -Glc was higher than that of 1 (Ka ≈ 3 × 10 M ). We considered that this difference was attributed to the following two factors. Firstly, electron-withdrawing carbonyl groups would enhance the hydrogen-bonding donor ability of the amino groups. Secondly, the helical structure of 2 could be stabilized by intramolecular hydrogen-bonding of the amido groups through the helical pitch.
Figure 1. Pyridine–acetylene–phenol and pyridine–acetylene–aniline oligomers.
References [1] a) Y. Ohishi, H. Abe, M. Inouye, Chem. Eur. J. 2015, 21, 16504−16511. b) Y. Ohishi, H. Abe, M. Inouye, Eur. J. Org. Chem. 2017, 6975−6979. c) H. Abe, C. Sato, Y. Ohishi, M. Inouye, Eur. J. Org. Chem. 2018, in press. DOI: 10.1002/ejoc.201800531.
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Symposium on Foldamers Bordeaux 2018 Poster P24
PolyProline type-I peptoid helices from a combination of -chiral and achiral N-substituted glycine monomers
Maha Rzeigui,a,b Claude Taillefumier,a Jamel Eddine Khiari,b Sophie Faure,a Olivier Roya
aUniversité Clermont Auvergne, CNRS, SIGMA Clermont, ICCF, F-63000 Clermont−Ferrand, France, bUniversité de Carthage, Faculté Des Sciences de Bizerte, Laboratoire de Chimie Organique et Analytique, ISEFC, 2000, Bardo, Tunisie [email protected]
Peptoids (N-substituted glycine oligomers) are an important class of foldamers capable of adopting a range of unique secondary structures based on the cis/trans geometries of their constituting main chain tertiary amide bonds.[1] Structural versatility of peptoids is also driven by the capacity of sequence- specific polypeptoids to form supramolecular assembly including bilayer nanosheets.[2] Examples of reported secondary structures for linear peptoids are the PolyProline-type I (PPI) and II helices,[3] the ribbon structure,[4] the peptoid square helix (η-helix),[5] and a zigzag pattern called ('sigma')-strand.[6] Since their backbones lack free NH amides, the capacity to form well-ordered structures is strictly related to the nature of the side chains, upon which the cis/trans peptoid amide equilibrium depends. In a recent past, great efforts have been devoted to controlling peptoid amide bond geometries through noncovalent interactions to minimize backbone conformational heterogeneity. For example, the bulky naphthylethyl (1npe)[7] and tertbutylethyl (1tbe)[8] -chiral side chains, or the achiral tBu[9] promote cis-amides and were used to generate stable all-cis PPI peptoid helices. We will report here on the synthesis and conformational study of oligopeptoids incorporating various proportions of site-specific chiral and achiral aliphatic cis-inducing side chains. The synthetic challenge of preparing conformationally homogeneous PPI helical peptoids with site-specific functionalised side chains will be also addressed.
References [1] Q. Sui, D. Borchardt, D. L. Rabenstein, J. Am. Chem. Soc. 2007, 129, 12042. [2] B. Sanii, R. Kudirka, A. Cho, N. Venkateswaran, G. K. Olivier, A. M. Olson, H. Tran, R. M. Harada, L. Tan, and R. N. Zuckermann, J. Am. Chem. Soc., 2011, 133, 20808-20815. [3] N. H. Shah, G. L. Butterfoss, K. Nguyen, B. Yoo, R. Bonneau, D. L. Rabenstein, and K. Kirshenbaum, J. Am. Chem. Soc. 2008, 130, 16622-16632. [4] J. A. Crapster, I. A. Guzei, and H. E. Blackwell, Angew. Chem. Int. Ed., 2013, 52, 5079-5084. [5] B. C. Gorske, E. M. Mumford, C. G. Gerrity, and I. Ko, J. Am. Chem. Soc., 2017, 139, 8070-8073. [6] R. V. Mannige, T. K. Haxton, C. Proulx, E. J. Robertson, A. Battigelli, G. L. Butterfoss, R. N. Zuckermann, and S. Whitelam, Nature, 2015, 526, 415-420. [7] J. R. Stringer, J. A. Crapster, I. A. Guzei, and H. E. Blackwell, J. Am. Chem. Soc., 2011, 133, 15559-15567. [8] O. Roy, G. Dumonteil, S. Faure, L. Jouffret, A. Kriznik, and C. Taillefumier, J. Am. Chem. Soc., 2017, 139, 13533- 13540. [9] G. Angelici, N. Bhattacharjee, O. Roy, S. Faure, C. Didierjean, L. Jouffret, F. Jolibois, L. Perrin, and C. Taillefumier, Chem. Commun., 2016, 52, 4573-4576.. [10] C. Caumes, O. Roy, S. Faure, and C. Taillefumier, J. Am. Chem. Soc., 2012, 134, 9553-9556.
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Symposium on Foldamers Bordeaux 2018 Poster P25
Directed Evolution and engineering of FN3-derived PSD-95 PDZ domains binders.
Charlotte Rimbault,a Kayshap Maruthi,b,c Christelle Breillat,a Camille Genuer,a Sara Crespillo,a Daniel Choquet,a,d Cameron D. Mackereth b,c & Matthieu Sainlos a
a Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience UMR 5297, Bordeaux, France1,bUniv. Bordeaux, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, Pessac, France, c Inserm U1212, CNRS UMR 5320, ARNA Laboratory, Univ. Bordeaux, 146 rue Léo Saignat, Bordeaux, France, d Bordeaux Imaging Center, UMS 3420 Centre National de la Recherche Scientifique, University of Bordeaux, US 4 INSERM, Bordeaux, France [email protected]
Identification of the molecular mechanisms involved in the regulation of glutamate receptor trafficking is crucial to our understanding of synaptic maturation and plasticity. In this context, the PDZ domain-mediated interactions of the AMPA-type glutamate receptors with the synaptic scaffold proteins from the PSD-95 family have been identified over the last decade as critical for their synaptic stabilization and their function. However, the mechanisms that dynamically govern their respective synaptic retention remain poorly understood. In order to investigate these PDZ domain-mediated interactions, we have exploited directed evolution methods to develop small synthetic binders based on the fibronectin type III domain (FN3), which constitutes a robust scaffold for antibody-like binding proteins. Our strategy relies on a selection approach by phage display to target independent protein modules such as the tandem PDZ domains of PSD-95-like proteins. The tools we have obtained were thoroughly characterized and later engineered to ultimately monitor or modulate interactions involving endogenous PSD-95 proteins.
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Symposium on Foldamers Bordeaux 2018 Poster P26
Synthesis of Helically Folded Quinoline Macrocycles
Ko Urushibara,a Yann Ferrand,b Hyuma Masu,c Kosuke Katagiri,d Masatoshi Kawahata,e, f Kentaro Yamaguchi,f Aya Tanatani,a Ivan Huc b, g aOchanomizu University, Bunkyo-ku, Tokyo, Japan, bCNRS, CBMN, Institut Europeen de Chimie et Biologie, Pessac, France, cChiba University, Inage-ku, Chiba, Japan, dKonan University, Kobe, Hyogo, Japan, eShowa Pharmaceutical University, Machida, Tokyo, Japan, fTokushima Bunri University, Shido, Kagawa, Japan, g Ludwig-Maximilians-Universität, München, Germany [email protected] / [email protected]
Various kinds of macrocycle have been developed so far and have great roles in the field of host- guest chemistry. Aromatic oligoamide strands fixed their conformation by intramolecular hydrogen bond and this feature makes their macrocycle adopt to take coplanar structure.[1] For example, oligoamides of 8-amino-2-quinolinecarboxylic acid adopt unusually stable helical structure.[2] As the cyclic derivatives, only cyclic trimer and tetramer were obtained so far in the process of polymerization of quinoline monomer.[3] Cyclic trimer has flat shape, while cyclic tetramer takes saddle-like strained structure. The formation of such strained structures is intriguing. However, longer helical oligomers than a pentamer cannot be denatured and do not form cycles. In this study, to synthesize larger cyclic quinolone oligoamides, tertiary amide bonds with cis form[4] were introduced to helical quinoline oligoamides. We expected that cis conformation produces the kink to helical oligoamides and facilitates the formation of macrocycles. As the N-substituent of tertiary amide bonds, 2,4-dimethoxybenzyl (DMB) group was chosen since it will be able to be easily removed after cyclization. We synthesized various lengths of oligoamide amino acids and investigated their cyclization conditions. As the result, we achieved the syntheses of cyclic pentamer, hexamer, and heptamer by introduction of proper numbers and positions of DMB groups on the amide bonds of the precursors for cyclization (Fig. 1). X-ray crystallography revealed their unique conformations. Both of cyclic pentamer and hexamer without DMB groups take helically twisted conformation. Cyclic pentamer adopts figure-of-eight conformation, in which one secondary amide bond exists in cis form and shows flexible conformational behavior in solution.[5] Cyclic hexamer takes helically double twisted conformation. On the other hand, cyclic heptamer has two helical turns. These results suggested that larger cyclic oligoamides than cyclic pentamer tend to form helical conformation and especially cyclic pentamer and heptamer have chiral structures.
Figure 1. Crystal structures of cyclic quinoline oligoamides.
References [1] a) X. Ki, X. Yuan, P. Deng, L. Chen, Y. Ren, C. Wang, L. Wu, W. Feng, B. Gong, L. Yuan, Chem. Sci. 2017, 8, 2091-2100; b) Y. -Y. Zhu, C. Li, G. -Y. Li, X. -K. Jiang, Z. -T. Li, J. Org. Chem. 2008, 73, 1745-1751; c) Y. Liu, J. Shen, C. Sun, C. Ren, H. Zeng, J. Am. Chem. Soc. 2015, 137, 12055-12063. [2] H. Jiang, J. -M. Léger, I. Huc, J. Am. Chem. Soc. 2003, 125, 3448-3449. [3] H. Jiang, J. -M. Léger, P. Guionneau, I. Huc, Org. Lett. 2004, 6, 2985-2988. [4] A. Tanatani, I. Azumaya, H. Kagechika, J. Synth. Org. Chem. Jpn. 2000, 58, 556-567. [5] K. Urushibara, Y. Ferrand, Z. Liu, H. Masu, V. Pophristic, A. Tanatani, I. Huc, Angew. Chem. Int. Ed. 2018, in press.
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Symposium on Foldamers Bordeaux 2018 Poster P27
Solid-Phase Synthesis of Membrane-Spanning Aib Oligomers
Francis Zieleniewski,a Prasun Kumar,a Jonathan Claydena and Derek N. Woolfsona,b,c
aSchool of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, UK bBrisSynBio, University of Bristol, Life Sciences Building, Tyndall Avenue, Bristol, BS8 1TQ, UK cSchool of Biochemistry, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, BS8 1TD, UK [email protected]
Membranes make compartmentalisation possible, allowing maintenance of non-equilibrium chemical states required for energy flow. It is necessary for membranes to be selectively permeable to both information and chemical material and nature uses several families of proteins as pores and ion channels. Recent work at the Universities of Bristol and Oxford has allowed the synthesis of new pore structures with inspiration from natural membrane-spanning proteins and artificial self- [1] associated -helices. The 310 helix may find use in building structures that self-associate into membrane-spanning structures. The 310 helix is rare in proteins, possessing a well-defined linear structure that forms when sequences contain a high proportion of hindered quaternary amino acids. [2] These helices are often found in membrane-active antibacterial peptides. 310 helices formed from aminoisobutyric acid (Aib) readily insert into membranes and, once embedded, have been shown to discharge a pH gradient across a membrane with activity dependant on foldamer length[3] and terminal functionality.[4]
Figure 1. Solid-phase synthesis and CD spectra of Aib-containing oligomers.
This work describes for the first time the use of solid-phase peptide synthesis to build Aib-containing oligomeric structures of lengths suited to membrane thickness (Figure 1), incorporating design features that allow transmembrane geometries to be adopted and promote association in the membrane phase. Preliminary studies have shown these structures adopt 310 helices in an aqueous environment and transition into an -helix in the presence of an organic solvent. It will be observed how these structures insert and associate in the membrane using electrophysiology techniques with further optimisation with regards to their pore-forming abilities.
References [1] K. R. Mahendran, A. Niitsu, L. Kong, A. R. Thomson, R. B. Sessions, D. N. Woolfson, H. Bayley, Nat. Chem. 2017, 9, 411–419. [2] S. Futaki, D. Noshiro, T. Kiwada, K. Asami, Acc. Chem. Res. 2013, 46, 2924–2933. [3] J. E. Jones, V. Diemer, C. Adam, J. Raftery, R. E. Ruscoe, J. T Sengel, M. I. Wallace, A. Bader, S. L. Cockroft, J. Clayden, S. J. Webb, J. Am. Chem. Soc. 2016, 138, 688–695. [4] C. Adam, A. D. Peters, M. G. Lizio, G. F. S. Whitehead, V. Diemer, J. A. Cooper, S. L Cockroft, J. Clayden, S. J. Webb, Chem. Eur. J. 2018, 24, 2249–2256.
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Symposium on Foldamers Bordeaux 2018 Poster P28
Self-assembly of Flexible Supermolecules with Endohedral Binding Sties towards Nanocontainers and Sensors
Cuilian Liu, Yann Garcia*, Michael Singleton*
Institute of Condensed Matter and Nanosciences, Université catholique de Louvain, Place Louis Pasteur 1 bte L4.01.02, Louvain-la-Neuve, Belgium. [email protected]
The development of complex self-assembled supramolecular systems with precise geometries and cavities, is an area that has seen significant advances in the last decades. Much research is now focused on developing these systems to encapsulate guest molecules for applications such as molecular sensing and as nanocontainers for stoichiometric and catalytic reactions[1]. The use of non- covalent interactions to generate bidentate ligands from ligand building blocks is now well established, and more recently it has been demonstrated that interactions between the substrate and the functional binding sites can lead to enhanced catalytic activity, unprecedented selectivity, and allows co-encapsulation of the substrate[2]. This approach could be viable for both small capsules that bind one guest molecule and larger spheres that can accommodate multiple guest molecules. As a class of molecules, 1,8-diazaanthracenes have been studied for both their photophysical and pharmaceutical applications, and have been used frequently in the development of aromatic oligoamide foldamers(AOF)[3]. In these AOF, the connection of 1,8-diazaanthracenes via an amide linkage gives a planar or close to planar system with intramolecular hydrogen bonding and electrostatic interactions between the amide groups and the nitrogen atoms of neighboring heterocyclic monomers. The size and connectivity in these monomers can be easily modified to change the curvature of the sequence and the groups present on the edges of the aromatic units. For self-assembly this allows access to changeable cavity size, and to the interior array of functional groups for guest binding. Herein, we report the design of two 1,8-diazaanthracenes containing AOF and their metal based self-assembly. NMR, MS, UV-Vis, and fluorescence spectroscopies and computational simulations support the formation of self-assembled flexible metallacycles, capsules and spheres with cooperative endohedral hydrogen-bond motifs. The potential for these molecules in the development of complex supramolecular nanocontainers and sensors (see figure below) is also discussed.
Figure 1. Self-assembly of supermolecules with cooperative endohedral binding sites and flexible cavities, A) M3L3bpy3 metallacycle, B) M2L4 capsule and C) M12L24
References [1] a) T. R. Cook, P. J. Stang, Chemical Reviews, 2015, 115, 7001-7045; b). H. Vardhan, M. Yusubov, F. Verpoort, Coordination Chemistry Reviews 2016, 306, 171-194. [2] Q.-Q. Wang, S. Gonell, S. H. A. M. Leenders, M. Dürr, I. Ivanović-Burmazović, J. N. H. Reek, Nature Chemistry 2016, 8, 225. [3] E. Yashima, N. Ousaka, D. Taura, K. Shimomura, T. Ikai, K. Maeda, Chemical Reviews 2016, 116, 13752-13990.
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Symposium on Foldamers Bordeaux 2018 Poster P29
Light Driven Conformational Control of Aromatic Oligoamide Foldamer
Bappaditya Gole,a Brice Kauffmann,b,c Victor Maurizot,a,b Yann Ferrand,a,b Ivan Huc.d
a University of Bordeaux, UMR 5248, CBMN; b CNRS, Institut Européen de Chimie et Biologie, Pessac, France; c UMS3033/US001, INSERM; d Department für Pharmazie, Ludwig-Maximilians- Universität, München, Germany. [email protected]
Helical foldamers, oligomers that can adopt a compact and folded conformation, may display complex dynamic conformational changes in solution.[1] Integration of stimuli responsive components into foldamers may provide means to control such conformational changes through external modulation, and thus give access to functions such as controlled guest release or applications in material science.[2] One such component is 1,8-diaza-anthracene which forms a stable anti-parallel photodimer upon light irradiation.[3] Recently, we have demonstrated parallel arrangement of several such motifs in novel helix-sheet-helix architectures.[4] In these cases, folding of the helix components overcomes local dipolar repulsions between aromatic layers that arise from the parallel arrangement of diaza-anthracenes in the sheets. This provided us an opportunity to explore photodimerization of diaza-anthracenes within the folded structures. Remarkably, the predefined arrangement of the diaza- anthracene in the sheets facilitates their parallel photodimerization. The shortest strand of the helix- sheet-helix series showed a dynamic conformational change in solution and crystallographic analysis revealed an unusual folding process (Figure 1). Similarly, a longer sequence with four diaza- anthracenes core has two stable conformers at room temperature. However, low temperature NMR studies demonstrated presence of exclusively one of those. In this contribution, we will elaborate how parallel photodimerization of diaza-anthracene through external light irradiation can control such dynamic conformational changes in solution.
Figure 1. Schematic representation of a helix-turn-helix foldamer showing a reversible photodimerization of diaza-anthracene units.
References [1] M. Horeau, G. Lautrette, B. Wicher, V. Blot, J. Lebreton, M. Pipelier, D. Dubreuil, Y. Ferrand, I. Huc, Angew. Chem. Int. Ed. 2017, 56, 6823. [2] Z. Yu, S. Hecht, Chem.Commun., 2016, 52, 6639. [3] E. Berni, C. Dolain, B. Kauffmann, J.-M. Léger, C. Zhan, I. Huc, J. Org. Chem. 2008, 73, 2687. [4] A. Lamouroux, L. Sebaoun, B. Wicher, B. Kauffmann, Y. Ferrand, V. Maurizot, I. Huc . J. Am. Chem. Soc. 2017, 139, 14668.
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Symposium on Foldamers Bordeaux 2018 Poster P30
Custom-tailored Self-assembled Nanotubes through Hierarchical Coupling of Cooperative Interactions
David González-Rodríguez* a,b Violeta Vázquez-González,a R. Chamorro,a Maria J. Mayoral,a Fátima Aparicioa
a Nanostructured Molecular Systems and Materials group, Departamento de Química Orgánica, Universidad Autónoma de Madrid, 28049, Madrid, Spain. b Institute for Advanced Research in Chemical Sciences (IAdChem), Campus UAM-CSIC, 28049, Madrid, Spain. [email protected]
Our project aims at establishing an unconventional and versatile strategy to prepare self-assembled nanotubes[1] whose size, shape, composition and function can be rationally predesigned and controlled at the nanoscale using concepts and tools of supramolecular chemistry (Figure 1). Cyclic tetramers are formed from 4 monomeric -conjugated subunits by H-bonding interactions between nucleobase directors.[4] A proper monomer preorganization affords high chelate cooperativities and thus high cyclization yields in solution[3] and onto surfaces.[4] When these cyclic species are subjected to supramolecular polymerization reactions, self-assembled nanotubes are formed via a nucleation- growth cooperative mechanism. By adjusting the monomer structure, we can not only reach an extraordinary degree of control on the tube diameter and pore coating, but also on the coupling between chelate and nucleation-growth cooperative processes. Depending on the complementary pair of nucleobase directors employed (i.e. G-C vs A-U), the cooperativity of the cyclotetramerization process may be greatly influenced.[3b] This effect, at the same time, can alter the supramolecular polymerization pathway, that can follow a mechanism in which the macrocycles stack on top of each other, as shown in Figure 1, or in which linear oligomers fold and grow into polymeric nanotubes.
1. Chelate Cooperativity Monomer
15-5 nm Parallel Directors 1 - 4 nm
G
C Perpendicular Directors
Nanotube Side View Nanotube 2. Nucleation-- Top View Growth Cyclic Tetramer Figure 1. Self-assembled nanotubes obtained by coupling cooperative interactions.
References [1] T. Shimizu, M. Masuda, H. Minamikawa, Chem. Rev. 2005, 105, 1401. [2] a) M. J. Mayoral, N. Bilbao, D. González-Rodríguez, ChemistryOpen 2016, 5, 10; b) M. J. Mayoral, C. Montoro- García, D. González-Rodríguez in Comprehensive Supramolecular Chemistry II, Elsevier: Oxford, 2017; 191. [3] a) C. Montoro-García, J. Camacho-García, A. M. López-Pérez, N. Bilbao, S. Romero-Pérez, M. J. Mayoral, D. González-Rodríguez, Angew. Chem. Int. Ed. 2015, 54, 6780; b) C. Montoro-García, J. Camacho-García, A. M. López-Pérez, M. J. Mayoral, N. Bilbao, D. González-Rodríguez, Angew. Chem. Int. Ed. 2016, 55, 223; c) C. Montoro-García, M. J. Mayoral, R. Chamorro, D. González-Rodríguez, Angew. Chem. Int. Ed. 2017, 56, 15649. [4] N. Bilbao, I. Destoop, S. De Feyter, D. González-Rodríguez, Angew. Chem. Int. Ed. 2016, 55, 659.
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Symposium on Foldamers Bordeaux 2018 Poster P31
Secondary structures of Peptoids in gas phase assessed by Ion Mobily Mass Spectrometry and Molecular Modeling
Sébastien Hoyasa,b, Vincent Lemaura, Perrine Weberb, Emilie Halinb, Julien De Winterb, Pascal Gerbauxb, Jérôme Cornila a Laboratory for Chemistry of Novel Materials, Center of Innovation and Research in Materials and Polymers, Research Institute for Science and Engineering of Materials, University of Mons, UMONS, 23 Place du Parc, 7000 Mons, Belgium, b Organic Synthesis & Mass Spectrometry Laboratory, Interdisciplinary Center for Mass Spectrometry (CISMa), Center of Innovation and Research in Materials and Polymers (CIRMAP), University of Mons, UMONS, 23 Place du Parc, 7000 Mons, Belgium [email protected]
Peptoids, or poly-N-substituted glycines are peptide reigioisomers and represent a class of peptido- mimetic polymers.[1] The characteristic feature of these molecules is the side chain appended to the amide nitrogen instead of the α-carbon, as it is found in peptides. This structural difference prevents peptoid backbone to interact through hydrogen bonds as does peptide backbone, which should prevent the formation of well-defined secondary structure.[1] Though peptoids can form stable secondary structures in solution, mainly helical,[2] and some other specific structures.[2] Peptoids have been successfully tested as chiral selectors in chiral column chromatography,[3] with the helical structure being supposed to be responsible for these properties. Nuclear Magnetic Resonance (NMR) and Circular Dichroism (CD) are currently the most widely used techniques to characterize peptoid secondary structures.[1-3] However, the structural information provided by these methods is averaged over all isomeric structures. In this context, Mass Spectrometry (MS) techniques, especially Ion Mobility MS (IMMS), may represent a suitable method to investigate the relationship between primary and secondary structures, when associated to computational chemistry to propose candidate structures and associate them to the experimental data [4]. We report here the association of molecular modelling and IMMS experiments for the study of (poly)peptoids bearing alkyl side chains. Molecular Mechanics and Dynamics (MM/MD) calculations with PEPDROID,[5] a reparameterized version of DREIDING forcefield,[6] have been carried out to generate candidate gaseous structures. Then these structures have been injected in the reference CCS (Collision Cross Sections) calculation program, MOBCAL,[7] using the Trajectory Method (TM) algorithm, to compute theoretical CCSth, further compared to experimental values (CCSexp). This allows defining of the gas phase structures of ionized (poly)peptoids and help bridging the primary secondary to secondary structure gap.
References [1] N. Gangloff, J. Ulbricht, T. Lorson, et al., Chem. Rev. 2016, 116, 1753 [2] K. Huang, C. Wu, T. Sanborn, et al., J. Am. Chem. Soc. 2006, 128, 1733 [3] H. Wu, T. Liang, C. Yin, et al., The Analyst 2011, 136, 4409 [4] J. De Winter, V. Lemaur, R. Ballivian, et al., Chem. Eur. J. 2011, 17, 9738 [5] S. Hoyas, V. Lemaur, Q. Duez, F. Saintmont, E. Halin, J. De Winter, P. Gerbaux, J. Cornil, 2018 (in preparation) [6] S. Mayo, B. Olafson and W. Godart, J. Phys. Chem. 1990, 94, 8897 [7] M. Mesleh, J. Hunter, A. Shvartsburg, et al., J. Phys. Chem. 1996, 100, 16082
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Symposium on Foldamers Bordeaux 2018 Poster P32
Studies on multi-layered biomimetics of lytic polysaccharide monooxygenases
Sarah Lam, Xiao Mu, Michael Singleton*
Institute of Condensed Matter and Nanosciences (Molecules, Solids and Reactivity) Université Catholique de Louvain. Place Louis Pasteur 1 bte L4.01.06 Louvain-la-Neuve, Belgium. [email protected]
Lytic polysaccharide monooxygenases (LPMO) are a class of copper-containing enzymes that catalyze oxidative cleavage of glycosidic bonds of recalcitrant polysaccharides.[1] Their active site consist of a copper ion coordinated in T-shaped geometry to one monodentate histadine residue and one bidentate N-methylated histadine through its imidazole side chain and N-terminal amine (Histadine brace). In certain types of LPMO (AA9/10s), either a tyrosine or phenylalanine is present in close proximity to the axial position. In order to gain a better understanding of the role of these structural elements in the catalytic oxidation mechanism, copper complexes with conformationally stable and predictable aromatic oligoamides have been designed to mimic the active site of LPMO. The effect of changes in the first coordination sphere groups such as the structure and sterics of the “histadine brace” on the catalytic activity will be examined. Complexes bearing longer aromatic olidgoamides that allows formation of a foldamer microenvironment will also be synthesized in order to study the effect of second coordination sphere groups on substrate binding and catalytic activity. The initial synthetic progress and perspectives of this work are described.
Figure 1. Example of oligoamide based biomimetic of lytic polysaccharide monooxygenase
References [1] G. R. Hemsworth, B. Henrissat, G. J. Davies, P. H. Walton, Nat. Chem. Biol. 2014, 10, 122–126.
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Symposium on Foldamers Bordeaux 2018 Poster P33
Screw-Sense Preference of 12/10-Helical -Peptides with Dynamic Folding Propensity
Guenhyuk Jang,a Min Kyung Kim,a Sojung Kim,a Hoyang Son,a Young Kee Kang,b and Soo Hyuk Choi*,a
aDepartment of Chemistry, Yonsei University, Seoul, 03722, Republic of Korea bDepartment of Chemistry, Chungbuk National University, Chungbuk, 28644, Republic of Korea [email protected]
The -peptide 12/10-helix is a type of mixed helices, in which two types of intramolecular hydrogen bonds with opposite directionality alternate along the helical axis. We have previously reported that oligomers of cis-2-aminocyclohexanecarboxylic acid (cis-ACHC) with alternating chirality adopt both right- and left-handed 12/10-helical conformations,[1] suggesting that the 12/10-helical backbone could be a new class of dynamic foldamer with switchable screw sense.[2] In that regard, we have explored diverse internal and external factors that may control the helical screw sense with a variety of examples: incorporation of a central residue with a specific constraint, modification of terminal capping, length of oligomers, solvent conditions, etc. In addition, relative stability and interconversion mechanism of the two opposite handed helices were analyzed by molecular modeling methods. These results could facilitate utilizing the 12/10-helical foldamer as a scaffold for stimuli- responsive functional oligomers.
References [1] S. Shin, M. Lee, I. A. Guzei, Y. K. Kang, S. H. Choi, J. Am. Chem. Soc. 2016, 138, 13390. [2] B. A. F. Le Bailly, J. Clayden, Chem. Commun. 2016, 52, 4852.
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Symposium on Foldamers Bordeaux 2018 Poster P34
Structural characterisation of a urea based foldamer in complex with a protein
Jérémie Burattoa, Laura Mauran,b Sébastien Goudreaub and Gilles Guicharda aUniversité de Bordeaux, CNRS, UMR 5248, CBMN, IECB, Pessac (France), bUREkA Sarl, Pessac (France) [email protected]
The p53 protein is a transcription factor that regulates the expression of many genes coding for proteins involved in various biological functions. This protein is the guarantor of cellular integrity. The level of p53 expression is highly controlled and kept low by a negative regulatory mechanism driven by the hDM2 protein.[1] The overexpression of the hDM2 protein has been observed in many cases of cancer. Thus, inhibiting the interaction between these proteins, in order to restore the activity of the p53 molecule is a strategy to fight against cancer.[2] The interaction between these two proteins is mediated by an α-helix located at the N-terminal extremity of the p53 protein.[3] α-Helices are key elements of biomolecular recognition as reflected by the fact that a large fraction of protein-protein complexes in the Protein Data Bank features helical interfaces.[4] However, short, isolated peptide helices are generally only weakly populated in aqueous environment and are susceptible to proteolytic degradation, thus limiting their therapeutic potential. A variety of chemical strategies have been proposed to increase the helix folding propensity and stability of α-peptides among which foldamer- based approaches have recently emerged. In this context, we became interested by the possibility to combine peptide and foldamer helical backbones in a single strand to generate new generations of α-helix mimics. We have shown that oligourea foldamer/peptide chimeras form well-defined helical structures in polar organic solvents with the propagation of a continuous intramolecular H-bond network spanning the entire sequence.[5]
Figure 1. a peptide/foldamer chimera obtained by capping a peptide (slate blue) with short oligourea segments (orange).
In this presentation, we describe the design of peptide/oligourea hybrid compounds with the ability to modulate the p53/hDM2 interaction, and report our efforts to structurally characterize the interactions between the most potent foldamers in this series and the target protein as a mean to improve design principles and generalize the discovery of foldamer-based inhibitors of protein- protein interactions.
References [1] A. Hock and K. H. Vousden, Int. J. Biochem. Cell Biol., 2010, 42, 1618–21 [2] P. Chène, Nat. Rev. Cancer, 2003, 3, 102–9 [3] P. H. Kussie et al., Science, 1996, 274, 948–53 [4] A.L. Jochim and P.S. Arora, ACS Chem. Biol., 2010, 5, 919–23 [5] J. Fremaux, et al., Angew. Chemie Int. Ed., 2015, 54, 9816–20
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Symposium on Foldamers Bordeaux 2018 Poster P35
Protein Hotspots Grafting by Dynamic Combinatorial Chemistry
Benjamin Zagiel,1,2 Taleen Peker,1,2 Emeric Miclet, 1,2 Emmanuelle Sachon 1,2 and Roba Moumné1,2 *
1 Sorbonne Universités, UPMC Univ. Paris 06, École normale supérieure, CNRS, Laboratoire des Biomolécules (LBM), 4 place Jussieu, 75005 Paris, France, 2 Laboratoire des Biomolécules, Département de chimie, École normale supérieure, UPMC Univ. Paris 06, CNRS, PSL Research University, 75005 Paris, France [email protected]
Small peptides are attractive but underexploited compounds that occupy an intermediate molecular space (1-2 kDa) between that of traditional drug-like compounds (<500 Da) and much larger biologics (>5000 Da). Because their sequence can be directly derived from proteins, they can closely reproduce their specific side-chains arrangement and should thus incarnate the simplest functional protein mimetic. However, when removed from their native context, peptide segments usually fail to adopt the bioactive conformation. This conformational freedom leads to entropic penalty upon binding and affects their affinity. To circumvent this, two fundamentally different tactics have been suggested. One consists in introducing conformational constraints into peptide sequence: backbone macrocyclization, side-chains cross-linking (stapled peptides), constrained amino acids surrogates or nucleating template.[1] The other one often called “grafting strategy” consists in “dissecting” the set of residues that make crucial contribution in a molecular recognition event, the so-called “hotspots”, and “grafting” them in the same arrangement on a stable 3D scaffold, leading thus to a miniature version of the larger proteins.[2] The limit of this strategy is that structural and mutagenesis data on the protein to mimic have to be available. In addition, it delivers a first low affinity hit, which is in turn optimized through cycles of design and screening, and in most cases this second task represents the most challenging step of the process. In order to bring a new alternative, we propose here to combine a small folded peptide scaffold and the use of dynamic combinatorial chemistry (DCC)[3] to decorate this scaffold with functional groups involved in the recognition of a relevant target. In such an approach grafting of a protein hotspots is performed by auto-assembly, directly driven by the molecular recognition of the peptide by its putative target.
Figure 1. Building of a well-ordered protein mimetic by DCC on a folded scaffold.
References [1] T. A. Hill, N. E. Shepherd, F. Diness, D. P. Fairlie, Angew. Chem. Int. Ed. 2014, 53, 13020–13041. [2] J. A. Wells, C. L. McClendon, Nature 2007, 450, 1001–1009. [3] Herrmann, A. Chem. Soc. Rev. 2014, 43, 1899; Y. Liu, J.-M. Lehn, A. K. H. Hirsch, Acc. Chem. Res. 2017, 50, 376.
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Symposium on Foldamers Bordeaux 2018 Poster P36
Copper (II) loaded oligo-quinolinecarboxamide foldamers and their charge transport
Jinhua Wang,a, b Barbara Wicher,a, b Alejandro Mendez-Ardoy,c Gilles Pecastaings,d Brice Kauffmann,a, e Thierry Buffeteau,c Dario Bassani*,c Victor Maurizot*,a, b Ivan Huc*a, b, f
a Univ. Bordeaux, CNRS, Institut Européen de Chimie et Biologie, Pessac, France;b UMR 5248, CBMN; c Institut des Sciences Moléculaires, CNRS UMR 5255, Univ. Bordeaux; d Inst. Polytechnique de Bordeaux CNRS UMR 5629 LCPO; e UMS3033/US001, INSERM; f Department für Pharmazie, Ludwig-Maximilians-Universität, München, Germany. [email protected]
Alignment of metal ions in one dimension is a model system for molecular wires which may have potential applications in molecular electronics. [1,2] However, the alignment of metal ions in one dimension is not trivial and requires the use of an external template with a fine control of different factors: inter and intramolecular forces and also geometry and shape of different blocks. The single helical structured oligo-quinolinecarobxamide foldamers [3] is a well suited platform to fulfil those requirements. Indeed, here, we present the methodology to load multiple copper (II) ions (up to 16) into these helices. It is interesting to observed that in the solid state, these helices packed on top of each other forming a long range alignment of Cu (II) ions in the crystals. The alignment of copper (II) ions allows formation of molecular wires using relatively simple compounds. In a subsequent step, grafting of these loaded molecules on gold surface has been investigated and proved to form self-assembled monolayers (SAM) as validated by PMIRRAS spectroscopy. Initial measurements of the charge transport across these Cu loaded molecules have been done with conductive AFM and compared to those obtained for the foldamers itself. [4] Preliminary results showed different behaviors compared with the molecules without loading coppers.
Figure 1. (a) carton representation of copper (II) loaded foldamers and formation of self-assembled monolayer on gold surface; (b) Schematic representation of the MOM junction prepared using C- AFM.
References [1] Neil Robertson, Craig A. McGowan, Chem. Soc. Rev. 2003, 32, 96-103. [2] Nunzio Tuccitto et al. Nat. Mater. 2009, 8, 41-46. [3] Jiang, H..; Léger, J.-M.; Huc, I. J. Am. Chem. Soc. 2003, 125, 3448-3449. [4] Alejandro Mendez-Ardoy, Nagula Markandeya, Ivan Huc, Dario M. Bassani et al. Chem. Sci., 2017, 8, 7251-7257.
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Symposium on Foldamers Bordeaux 2018 Poster P37
Dynamic Molecules with Switchable Hydrogen-Bond Directionality
David T. J. Morris, John W. Ward, David P. Tilly, Jonathan Clayden
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS [email protected]
Nowick and co-workers have reported that ethylene-bridged triureas can be synthesised with complete conformational control by judicious use of steric hindrance and hydrogen-bonding.[1] The concept of complete but switchable conformational control of these structures has not been investigated and is of interest as it gains access to dynamic peptide mimics with switchable hydrogen- bond directionality (HBD). Previous work in the Clayden group has shown that achiral oligourea-derived foldamers can communicate stereochemical information by inducing a helical excess with a chiral ligand.[2-4] This served as the first example of reversible HBD. In our design, the global HBD of an ethylene- bridged oligourea foldamer can be controlled by applying an electronic bias at one terminus. The orientation of the final urea can be inferred by variable-temperature 1H NMR and nOe studies. The HBD of these foldamers can be switched by employing a terminal pyridine, which reorients the adjacent urea upon protonation. This reorientation is communicated as binary information throughout the rest of the foldamer, resulting in a global HBD switch. The switching process has also been successfully demonstrated with the light-induced photo-dissociation/association of a photoacid.[5] Investigations into HBD switchable foldamers with binding sites complementary to that of DNA nucleobases are currently ongoing. Different spectroscopic or chemical outputs at the reporting terminus are also being explored. Ethylene-bridged oligoureas represent a new class of foldamers that can undergo a global HBD switch in response to pH change or exposure to light, and could be amenable to DNA ligand binding. The concept of switching hydrogen-bonding directionality in foldamers is a significant simplification of how biological systems store and communicate information and could provide access to interesting and useful chemical and biomimetic functions.
Figure 1. Dynamic hydrogen-bond-directionality switchable oligoureas.
References [1] J. S. Nowick, S. Mahrus, E. M. Smith, J. W. Ziller, J. Am. Chem. Soc. 1996, 118, 1066-1072. [2] L. Byrne, J. Solà, T. Boddaert, T. Marcelli, R. W. Adams, G. A. Morris, J. Clayden, Angew. Chem. Int. Ed. 2014, 53, 151-155. [3] J. Brioche, S. J. Pike, S. Tshepelevitsh, I. Leito, G. A. Morris, S. J. Webb, J. Clayden, J. Am. Chem. Soc. 2015, 137, 6680-6691. [4] R. Wechsel, J. Raftery, D. Cavagnat, G. Guichard, J. Clayden, Angew. Chem. Int. Ed. 2016, 55, 9657-9661. [5] Z. Shi, P. Peng, D. Strohecker, Y. Liao, J. Am. Chem. Soc. 2011, 133, 14699-14703.
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Symposium on Foldamers Bordeaux 2018 Poster P38
De novo designed proteins catalyzing amide bond forming reactions
Elise Naudin,a William DeGradob and Vladimir Torbeeva
aInstitut de Science et d’Ingénierie Supramoléculaires, UMR 7006, Université de Strasbourg, 8 allée Gaspard Monge, 67000 Strasbourg, France [email protected] bDepartment of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA [email protected]
Chemical synthesis of peptides and proteins is of great interest as a tool for studying protein structure and function and as a method for preparation of biomedically important proteins.[1] Our goal is to design de novo proteins which can accelerate the amide bond forming reactions and can be used as peptide ligases or for peptide/protein labelling. In this study, we explored N-terminus of α-helix with unpaired hydrogen-bond donors as a structural motif to stabilize negatively charged tetrahedral intermediates of nucleophilic addition-elimination reactions at carbonyl group (Figure 1). Cysteine residue acting as a principal nucleophile was engineered at either of the two key positions, so-called Ncap (residue preceding the first amino acid that adopts α-helical conformation) and N2 (second residue at N-terminus of α-helix) in a designed Domain-Swapped Dimer (DSD) three-α-helix protein scaffold.[2] We demonstrated efficient transthioesterification of peptide-αthioesters and, subsequently, aminolysis of the thioester intermediate in the presence of a large excess of tris(hydroxymethyl)aminomethane (Tris), an amine with pKa similar to N-terminal amino group of peptides. To improve catalytic parameters, the iterations of computational design, X-ray crystallographic structural studies, as well as combinatorial synthesis of libraries of variants are currently undergoing.
Figure 1. a) Three-dimensional structure of the DSD protein. Catalytic site at N-terminus is located in the black box. b) Catalytic mechanism of peptide ligation in the presence of putative enzyme.
References [1] D. J. Craik, D. P. Fairlie, S. Liras, D. Price, Chem. Biol. Drug Des. 2013, 81, 136–147. [2] N. L. Ogihara, G. Ghirlanda, J.W. Bryson, M. Gingery, W. F. DeGrado, D. Eisenberg, Proc. Natl. Acad. Sci. 2001, 98, 1404–1409.
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Symposium on Foldamers Bordeaux 2018 Poster P39
Low pH-responsive cyclic ,-disubstituted -amino acids for controlling secondary structures of peptide foldamers
Makoto Oba,a Kaori Furukawa,a Kotomi Toyama,a George Ouma Opiyo,a Yosuke Demizu,b Masaaki Kurihara,c Mitsunobu Doi,d Masakazu Tanakaa
aGraduate School of Biomedical Sciences, Nagasaki University, bDivision of Organic Chemistry, National Institute of Health Sciences, cDepartment of Pharmaceutical Sciences, International University of Health and Welfare, dOsaka University of Pharmaceutical Sciences [email protected]
,-Disubstituted -amino acids (dAAs) are promising tools for design of peptide foldamers.[1] Peptides containing cyclic dAAs are known to adopt a helical structure.[2] In contrast, peptides composed of acyclic dAAs with two bulky substituents equal to or larger than ethyl groups form extended planar C5 conformations.[3] Accordingly, changes in side chain structures of dAAs from a cyclic to an acyclic structure in peptides may lead to changes in peptide secondary structures from a helical to a planar or random structure. In the current study, we designed cyclic dAAs possessing a cyclic acetal in the side chain. A cyclic acetal is hydrolyzed by an acidic treatment and gives an acyclic diol. We incorporated cyclic dAAs into L-leucine sequences and studied their preferred secondary structures before and after an acidic treatment. Conformational changes in peptides in response to low pH were clarified (Figure 1).[4]
R R' O O OH OH O O O O O O O O H H H H H H Ac-HN N N N Ac-HN N N N N N N N CO2Me N N N N CO2Me H H H H H H H H O O O O O O O O OH OH R R' acyclic diol cyclic acetal
Acidic treatment
Conformational change
Helical structure Random structure Figure 1. Conformational changes in peptides containing cyclic dAAs by an acidic treatment.
References [1] a) M. Tanaka, Chem. Pharm. Bull. 2007, 55, 349; b) M. Crisma, C. Toniolo, Biopolymers (Pept. Sci.) 2015, 104, 46. [2] a) P. K. C. Paul, M. Sukumar, R. Bardi, A. M. Piazzesi, G. Valle, C. Toniolo, P. Balaram, J. Am. Chem. Soc. 1986, 108, 6363; b) M. Oba, H. Takazaki, N. Kawabe, M. Doi, Y. Demizu, M. Kurihara, H. Kawakubo, M. Tanaka, J. Org. Chem. 2014, 79, 9125. [3] a) M. Tanaka, S. Nishimura, M. Oba, Y. Demizu, M. Kurihara, H. Suemune, Chem. Eur. J. 2003, 9, 3082; b) C. Peggion, A. Moretto, F. Formaggio, M. Crisma, C. Toniolo, Biopolymers (Pept. Sci.) 2013, 100, 621. [4] K. Furukawa, M. Oba, K. Toyama, G. O. Opiyo, Y. Demizu, M. Kurihara, M. Doi, M. Tanaka, Org. Biomol. Chem. 2017, 15, 6302.
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Symposium on Foldamers Bordeaux 2018 Poster P40
Electron transfer in helical oligourea foldamers
Karolina Pulka-Ziach,a Anna Puszko,a Joanna Juhaniewicz-Debinska,b Slawomir Sekb
a Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland, b Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Zwirki i Wigury 101, 02-089, Warsaw, Poland [email protected]
Electron transfer (ET) phenomenon is a fundamental reaction in Nature, playing a role in photosynthesis, enzymatic reactions, drug activations and the other key biological processes.[1] -Helical peptides are known as mediators of this process,[2] but their use as model compounds is limited to molecules longer that 10 residues. To overcome this drawback -helicomimetic oligourea [3] foldamers with general formula [-CH(R)-CH2-NH-CO-NH]n were synthesized in solution and on the solid support. Such compounds are known to adopt robust 2.5-helical conformation. Only four residues are enough to form stable 1.5 helical turns. [4] We will show two families of different chain length compounds (2-12 residues) with thiol group attached to + or - helix dipole pole. The helicity of oligoureas was confirmed in solution and also after the formation of self-assembled monolayers on the gold surface. Such systems were used to study the electron transfer process by current sensing atomic force microscopy (CS-AFM).[5] We showed that oligoureas are good electron transfer mediators and, because of the conformational stability, they may act as excellent models to study the dependence of the mechanism of electron transfer process on the length of the mediator.
References [1] M. Cordes, B. Giese, Chem Soc Rev, 2009, 38, 892. [2] J. Pawlowski, J. Juhaniewicz, D. Tymecka, S. Sek, Langmuir, 2012, 28, 17287. [3] G. Guichard, I. Huc, Chem Commun, 2011, 47, 5933. [4] L. Fischer, G. Guichard, Org Biomol Chem, 2010, 8, 3101. [5] K. Pulka-Ziach, S. Sęk, Nanoscale, 2017, 9, 14913.
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Symposium on Foldamers Bordeaux 2018 Poster P41
In Vitro Translation of aromatic oligoamide foldamers
Christos Tsiamantas,a Sunbum Kwon,b Joseph M. Rogers,a Simon J. Dawson,b Pradeep K. Mandal,b Hiroaki Suga,a Ivan Hucb
a Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo, Japan, b Department of Pharmacy, Ludwig-Maximilians-Universität, München, Germany [email protected], [email protected]
In vitro, flexible tRNA aminoacylation ribozymes, known as flexizymes, have enabled charging of non-canonical amino acids onto tRNA molecules.[1] Subsequent addition to a solution containing the essential components of an in vitro translation system enables the assembly of mRNA-encoded peptides, equipped with various building blocks. D-amino acids, N-alkyl amino acids, fluorescent/ biotin labeled amino acids and exotic peptides among others have been successfully incorporated.[2] Coupling of the above technology with mRNA display has yielded numerous scaffolds manifesting enormous potential in drug discovery and imaging.[3] This presentation will focus on recent advances on the incorporation of aromatic oligoamide foldamers into peptides, taking advantage of nature's translational machinery. It was recently shown that oligoamides may successfully initiate the translation of foldamer-peptide hybrid molecules.[4] Recent progress not only includes an expanded scope of substrates for initiation, but also show that foldamers may be included into appendages in peptide elongation. Our findings pave the way to introducing foldamers in mRNA display, with a whole new range of attributes to be discovered.
Figure 1. a) Chemical formulas of the CME-activated amino acids used for translation initiation and elongation, CME circled in orange. b) Schematic representation of the in vitro translation system. The orange and blue sphere following the helical segment are Gly and Phe, respectively.
References [1] H. Murakami, A. Ohta, H. Ashigai, H. Suga, Nat. Methods 2006, 3, 357 − 359 [2] J. M. Rogers, H. Suga, Org. Biomol. Chem. 2015, 13, 9353 − 9363 (review) [3] C. J. Hippolito, H. Suga, Curr. Opin. Chem. Biol. 2012, 16, 196 − 203 (review) [4] J. M. Rogers, S.Kwon, S. J. Dawson, P. K. Mandal, H. Suga, I. Huc, Nat. Chem. 2018, 10, 405 − 412
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Symposium on Foldamers Bordeaux 2018 Poster P42
Asymmetric 1,4-addition reactions of malonates to cyclic enones catalyzed by helical peptide foldamers
Tomohiro Umeno,a Atsushi Ueda,a Takuma Kato,b Mitsunobu Doi,b Masakazu Tanakaa
aGraduate School of Biomedical Sciences, Nagasaki University bOsaka University of Pharmaceutical Sciences [email protected]
Chiral organocatalysts have attracted much attention, and many types of aminocatalysts have been developed. Peptides are some of the potential aminocatalysts because of the amino group on the N terminus. Most of the peptide catalysts possess a specific secondary structure, such as an α-helix and a β-turn. We have already reported the highly enantioselective Juliá-Colonna epoxidation of α,β- unsaturated ketones using -helical L-Leu-based peptide foldamers stabilized by α,α-disubstituted α- amino acid (dAA).[1] Also, we reported the asymmetric Michael addition reactions of nitroalkane or dialkyl malonate to ,-unsaturated ketones by using helical-peptide foldamers as organocatalysts.[2] At that time, we noticed that the helical peptide having a cyclic dAA catalyzed highly enantioselective 1,4-addition reactions of dialkyl malonates to cyclic ,-unsaturated ketones, although usually a small chiral amino-organocatalyst could not be applied to the highly enantioselective 1,4-addition reactions to various ring size of cyclic enones.[3] We herein describe helical peptide foldamer-catalyzed asymmetric 1,4-addition reactions of dialkyl malonates to cyclic ,-unsaturated ketones. After the optimization of peptide catalysts and reaction conditions, the highly enantioselective reaction was accomplished in the case of cyclic enones (Figure 1). Also, the helical structure of peptide foldamer in the crystal state was confirmed by using X-ray crystallographic analysis.
H O H O H N N OMe N 2H 4 O O RO2C CO2R
+ RO2C CO2R n Helical Peptide Catalyst n O n = 0, 1, 2 R = Bn, Me, Et, iPr n = 0: >94% ee n = 1: >97% ee n = 2: >98% ee Figure 1. Asymmetric 1,4-addition reactions of malonates to cyclic enones.
References [1] M. Nagano, M. Doi, M. Kurihara, H. Suemune, M. Tanaka, Org. Lett. 2010, 12, 3564−3566. [2] A. Ueda, T. Umeno, M. Doi, K. Akagawa, K. Kudo, M. Tanaka, J. Org. Chem. 2016, 81, 6343–6356. [3] V. Wascholowski, K. R. Knudsen, C. E. T. Mitchell, S. V. Ley, Chem. Eur. J. 2008, 14, 6155–6165. M. Yoshida, M. Narita, S. Hara, J. Org. Chem. 2011, 76, 8513–8517. M. Moritaka, N. Miyamae, K. Nakano, Y. Ichikawa, H. Kotsuki, Synlett 2012, 23, 2554–2558.
Poster P43
Stabilizing and Understanding a Miniprotein by Rational Design
Kathryn L. Porter Goff,a Christopher Williams,a,b Emily G. Baker,a Debbie Nicol,a Jenny L. Samphire,a Frank M. Zieleniewski,a Matthew P. Crump,a,b Derek, N. Woolfsona,b,c
aSchool of Chemistry, University of Bristol, Bristol BS8 1TS, UK bBrisSynBio, University of Bristol, Life Sciences Building, Tyndall Avenue, Bristol, BS8 1TQ, UK cSchool of Biochemistry, University of Bristol, Bristol BS8 1TD, UK [email protected]
The primary sequence of amino acids in a polypeptide chain determines a proteins 3D shape, how it folds and its function. Understanding this process is known as the protein-folding problem. The loss of conformational entropy upon folding must be overcome through the formation of many weak but cooperative non-covalent interactions. Studying miniproteins reduces the complexity of the problem and allows us to probe contributions to protein folding and stability.[1] Previously, we have described the fragment-based design of a 34-residue miniprotein, PP.[2] PP comprises a polyproline-II helix-loop- helix conformation. The helices were borrowed from the bacterial adhesin AgI/II and a loop from the pancreatic polypeptide. PP is monomeric in aqueous solution and reversibly unfolds with a midpoint unfolding temperature (TM) of 39 ˚C. The NMR structure reveals that PP is stabilized by the interdigitation of proline and tyrosine residues from the two helices and numerous CH- interactions. In this work, we move away from a fragment-based design approach (where the component parts come from natural proteins) with the desire to test generic rules for the fold by de novo design. We optimize the PP fold by rational redesign to give optimized-PP (oPP) which has a completely de novo framework and significantly enhanced thermal stability. We probe various general and intimate side chain-side chain interactions, revealing sequence-to-structure relationships for this miniprotein fold.[3]
Figure 1. (A, B) Helical wheel representations of the two helices in PP (A) and oPP (B). (C, D) NMR structures of PP and oPP, respectively. CH– interactions are highlighted (yellow).
References [1] E. G. Baker, C. Williams, K. L. Hudson, G. J. Bartlett, J. W. Heal, K. L. Porter Goff, R. B. Sessions, M. P. Crump, D. N. Woolfson, Nat. Chem. Biol., 2017, 13, 764. [2] E. G. Baker, G. J, Bartlett, K. L. Porter Goff, D. N. Woolfson, Acc. Chem. Res., 2017, 50, 2085. [3] K. L. Porter Goff, C. Williams, E. G. Baker, D. Nicol, J. L. Samphire, F. M. Zieleniewski, M. P. Crump, D. N. Woolfson, manuscript in preparation.
Poster P44
Exploring δ-Amino Acids to Design Novel Peptide Foldamers and Biomaterials
Rahi M. Reja,a Vivek Kumar,a Rajat Patel,a Hosahudya N. Gopia*
aDepartment of Chemistry, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pashan, Pune-411 008. [email protected]
Over the last two decades, backbone homologated α-amino acids such as β- and γ-amino acids have been extensively explored as building blocks to design various types of functional foldamers. In contrast to the β- and γ-peptides, foldamers constituted with δ-amino acids have been less explored, probably due to the difficulties in the synthesis of enantiopure δ-amino acids as well as issues related to the solubility of δ-peptide foldamers. Instructively, δ-amino acids can be used as mimics of α- dipeptides. In this context, we have designed new δ-amino acids encompassing “O” atom in the backbone, β-oxy δ-amino acids, and explored their utility in the design of novel foldamers and biomaterials. In contrast to the δ-peptides with complete carbon backbone, δ-peptides with β-oxy δ- amino acids have showed better solubility in organic solvents. In this poster, I will discuss the synthesis of β-oxy δ-amino acids composed of proteinogenic amino acid side chains, their utility as single residue β-turns to design β-hairpins, hybrid peptide helices and cyclic peptide nanotubes as transmembrane ion channels.
Figure 1.Utilisation of δ-amino acid for the design of novel peptide foldamers and biomaterials.
References [1] a) S. H. Gellman, Acc. Chem. Res.1998, 31, 173-180; b) J. Venkatraman, S. C. Shankaramma, P. Balaram, Chem. Rev.2001, 101, 3131-3152; c) G. Guichard, I. Huc, Chem. Commun. 2011, 47, 5933-5941; d) Foldamers: Structure, Properties and Applications (Eds.: S. Hecht, I. Huc), Wiley-VCH, Weinheim, 2007; e) J. A. Robinson, Acc. Chem. Res. 2008, 41, 1278-1288.
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Symposium on Foldamers Bordeaux 2018 Poster P45
Design and Synthesis of Biomimetic Metalloenzyme Active Sites with Oligoamide Scaffolds
Xiao Mu, Jérémie Bourotte, Olivier Riant, Michael L. Singleton*
Institute of Condensed Matter and Nanosciences (Molecules, Solids and Reactivity), Place Louis Pasteur 1 bte L4.01.06 Louvain-la-Neuve, Belgium. [email protected]
Lytic polysaccharide monooxygenases (LPMO) are copper-containing metalloenzymes that oxidatively cleave the glycosidic linkages in polysaccharides via C-H oxidation.1 The active site of LPMO (Figure 1a and 1b) contains a single copper atom in a T-shaped N3 coordination environment known as the histidine brace. This structural motif is conserved across all members of LPMO and yet its role in the oxidative power of these enzymes is still not well understood. In part, this results from the lack of synthetic model systems that can replicate this first coordination sphere, allowing detailed study of this ligand set. The problem here is that typical ligands for coordination chemistry allow the metal to control a large part of the coordination geometry. A system that could provide a structurally stable pre-organized binding site would greatly advance the design of biomimetic models. This poster describes our approach towards the use of folded organic scaffolds for generating pre- organized binding sites for metal complexes. Through the functionalization of an oligoamide scaffold with imidazole and histamine groups, the histidine brace motif, including the trans-imidazole and fixed primary amine (Figure 1c & 1d) can be mimicked. The initial synthetic progress for this project and the potential to functionalize the scaffold to study second coordination sphere interactions is described. Through this work our goal is to delineate the precise role of the histidine brace on the metal-based reactivity.
Figure 1. a,b) Active site structure of LPMO and Chemdraw representation. c,d) Chemdraw representations of foldamer based scaffolds.
References [1] Hemsworth G.R., Henrissat B., Davies G.J. & Walton P.H., Nat. Chem. Biol. 2014, 10, 122.
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Symposium on Foldamers Bordeaux 2018
List of Participants
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Symposium on Foldamers Bordeaux 2018 AGUESSEAU Julie Université de Montpellier, France [email protected] P19 AITKEN David Université Paris-Sud, France [email protected] ANDERSON Harry Oxford University, UK [email protected] KL4 APARICIO HERNANDEZ Fatima Universidad Autónoma de Madrid, Spain [email protected] P6 ATCHER Joan Ludwig-Maximilians-Universität München, Germany [email protected] P5 BASSANI Dario Université de Bordeaux, France [email protected] BAUTISTA Oscar Mauricio Université Catholique de Louvain, Belgium [email protected] P20 BORNERIE Mégane Université de Bordeaux, France [email protected] P3 BOULLOY Alice Université de Bordeaux, France [email protected] BOUROTTE Jérémie Université Catholique de Louvain, Belgium [email protected] P16 BURATTO Jérémie Université de Bordeaux, France [email protected] P34 CHAKRABORTY Tushar Kanti Indian Institute of Science, India [email protected] SL9 CHOI Soo Hyuk Yonsei University, South Korea [email protected] P33 CLAYDEN Jonathan University of Bristol, UK [email protected] PL1 COBB Alexander King's College London, UK [email protected] COMPAIN Guillaume Université de Bordeaux, France [email protected] CORVAGLIA Valentina Ludwig-Maximilians-Universität München, Germany [email protected] SL3 CSEKEI Marton Servier Research Institute of Medicinal Chemistry, Hungary [email protected] CUSSOL Léonie Université de Bordeaux, France [email protected] DE RICCARDIS Francesco University of Salerno, Italy [email protected] SL2 DEMIZU Yosuke National Institute of Health Sciences, Japan [email protected] P7 DOLAIN Christel Université de Bordeaux, France [email protected] DONG Zeyuan Jilin University, China [email protected] SL19 DUBREUIL Didier Université de Nantes, France [email protected] DUWEZ Anne-Sophie University of Liege, Belgium [email protected] SL20 EDWARDS Alison University of Kent, UK [email protected] P2 FAOUR Lara Moltech-Anjou Laboratory, France [email protected] P17 FAURE Sophie Université Clermont-Auvergne, France [email protected] P18 FERRAND Yann Université de Bordeaux, France [email protected] FISCHER Lucile Université de Bordeaux, France [email protected] FREMAUX Juliette UREkA - ImmuPharma Group, France [email protected] GAMBOA Stefani Université de Bordeaux, France [email protected]
GELLMAN Samuel University of Wisconsin - Madison, USA [email protected] KL3 GIRDHAR Ravi Protein Technologies, Inc, USA [email protected] GIUSEPPONE Nicolas Université de Strasbourg, France [email protected] KL7 GOLE Bappaditya University of Bordeaux, France [email protected] P29 GONZALEZ RODRIGUEZ David Universidad Autonoma de Madrid, Spain [email protected] P30 GOPALAKRISHNAN Ranganath AstraZeneca, Sweden [email protected] GOUDREAU Sebastien UREkA - ImmuPharma Group, France [email protected] SL5 GUICHARD Gilles Université de Bordeaux, France [email protected] HARTLEY Scott Miami University, USA [email protected] KL9 HEINIS Christian Ecole Polytechnique Fédérale de Lausanne, Switzerland [email protected] KL8 HÖBARTNER Claudia Julius-Maximilians-Universität Würzburg, Germany [email protected] KL1 HOYAS Sébastien UMONS, Belgium [email protected] P31 HUC Ivan Ludwig-Maximilians-Universität München, Germany [email protected] IMAI Hideto Japan Analytical Industry Co., Japan [email protected] KAUFFMANN Brice Université de Bordeaux, France [email protected] KNIPE Peter Queen's University Belfast, UK [email protected] SL1 KOEHLER Victor Université de Bordeaux, France [email protected] KOTSCHY Andras Servier Research Institute of Medicinal Chemistry, Hungary [email protected] KRISHNENDU Maji Université de Bordeaux, France [email protected] KUMAR Sunil New York University, USA [email protected] P13 LAM Yan Yu Sarah Université Catholique de Louvain, Belgium [email protected] P32 LAMOUROUX Arthur Université de Bordeaux, France [email protected] LI Zigang Peking University Shenzhen, China [email protected] SL13 LIU Cuilian Université Catholique de Louvain, Belgium [email protected] P28 LIU David Harvard University, USA [email protected] PL2 LIU Yazhou Université Catholique de Louvain, Belgium [email protected] P4 LIU Zhiwei University of the Sciences, USA [email protected] MAAYAN Galia Technion - Israel Institute of Technology, Israel [email protected] SL16 MACKERETH Cameron Université de Bordeaux, France [email protected] MAILLARD ludovic Université de Montpellier, France [email protected] MARTINEK Tamás Attila University of Szeged, Hungary [email protected] SL15
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Symposium on Foldamers Bordeaux 2016 MASSIP Stéphane Université de Bordeaux, France [email protected] MATAM LOSERY Stanly Paul University of Szeged, Hungary [email protected] MATEO-ALONSO Aurelio University of the Basque Country, Spain [email protected] SL6 MATEUS Pedro Université de Bordeaux, France [email protected] P15 MAURAN Laura UREkA-ImmuPharma Group, France [email protected] P34 MAURIZOT Victor Université de Bordeaux, France [email protected] MAZZIER Daniela Ludwig-Maximilians-Universität, Germany [email protected] P21 MCCLENAGHAN Nathan University of Bordeaux, France [email protected] P12 MEISEL Joseph New York University, USA [email protected] SL17 MERLET Eric Université de Bordeaux, France [email protected] MILLER Scott Yale University, USA [email protected] PL4 MORRIS David University of Bristol, UK [email protected] P37 MOUMNÉ Roba Sorbonne Université, France [email protected] P35 MU Xiao Université Catholique de Louvain, Belgium [email protected] P45 NAUDIN Elise University of Strasbourg, France [email protected] P38 NICOL Debbie University of Bristol, UK [email protected] P8 NITSCHKE Jonathan University of Cambridge, UK [email protected] PL5 OBA Makoto Nagasaki University, Japan [email protected] P39 ODA Reiko Université de Bordeaux, France [email protected] OHISHI Yuki University of Toyama, Japan [email protected] P23 OHWADA Tomohiko The University of Tokyo, Japan [email protected] SL18 OLSEN Christian University of Copenhagen, Denmark [email protected] KL6 PASCO Morgane Université de Bordeaux, France [email protected] PENTELUTE Bradley MIT, USA [email protected] SL4 PERDRIAU Camille Université de Bordeaux, France [email protected] P22 PETERSSON E. James University of Pennsylvania, USA [email protected] SL12 POPHRISTIC Vojislava University of the Sciences, USA [email protected] SL7 PORTER GOFF Kathryn University of Bristol, UK [email protected] P43 POST Saireddy Université de Bordeaux, France [email protected] P9 PULKA-ZIACH Karolina University of Warsaw, Poland [email protected] P40 REJA Rahi Masoom Indian Institute of Science Education and Research Pune, India [email protected] P44
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Symposium on Foldamers Bordeaux 2016 RIMBAULT Charlotte Université de Bordeaux, France [email protected] P25 RZEIGUI Maha Université de Clermont-Auvergne, France [email protected] P24 SAINLOS Matthieu Université de Bordeaux, France [email protected] SALGADO Gilmar Université de Bordeaux, France [email protected] SAWADA Tomohisa The University of Tokyo, Japan [email protected] SL10 SCHAFMEISTER Christian Temple University, USA [email protected] SL8 SERPELL Christopher University of Kent, UK [email protected] SL21 SINGLETON Michael Université Catholique de Louvain, Belgium [email protected] SLEIMAN Hanadi McGill University, Canada [email protected] PL3 SNAPE Tim University of Central Lancashire, UK [email protected] SRIVASTAVA Aasheesh IISER Bhopal, India [email protected] P1 TAILLEFUMIER CLAUDE Université de Clermont-Auvergne, France [email protected] TANATANI Aya Ochanomizu University, Japan [email protected] SL14 TEZCAN Akif University of California, San Diego, USA [email protected] KL2 THOMPSON Sam University of Southampton, UK [email protected] TOKOLI Attila University of Szeged, Hungary [email protected] P14 TSIAMANTAS Christos University of Tokyo, Japan [email protected] P41 UMENO Tomohiro Nagasaki University, Japan [email protected] P42 URUSHIBARA Ko Ochanomizu University, Japan [email protected] P26 VENIN Claire UREkA, France [email protected] WANG Jinhua Université de Bordeaux, France [email protected] P36 WATERS Marcey University of North Carolina at Chapel Hill, USA [email protected] KL5 WEBER Perrine UMONS, Belgium [email protected] WILSON Andrew University of Leeds, UK [email protected] YAMAGAMI Motoya The University of Tokyo, Japan [email protected] P11 YAMAGUCHI Masahiko Tohoku University, Japan [email protected] SL11 YAO ChenHao Université de Bordeaux, France [email protected] YOO Sung Hyun Université de Bordeaux, France [email protected] ZHANG Lianjin University of Bordeaux, France [email protected] ZIELENIEWSKI Francis University of Bristol, UK [email protected] P27 ZWILLINGER Marton Servier Research Institute of Medicinal Chemistry, Hungary [email protected] P10
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Symposium on Foldamers Bordeaux 2016