DOCSLIB.ORG

Peptidomimetic Polymers: Advances in Monomer Design and Polymerization Methods Brandon Andrew Chan Louisiana State University and Agricultural and Mechanical College

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Peptidomimetic Polymers: Advances in Monomer Design and Polymerization Methods Brandon Andrew Chan Louisiana State University and Agricultural and Mechanical College Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 2016 Peptidomimetic Polymers: Advances in Monomer Design and Polymerization Methods Brandon Andrew Chan Louisiana State University and Agricultural and Mechanical College Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_dissertations Part of the Chemistry Commons Recommended Citation Chan, Brandon Andrew, "Peptidomimetic Polymers: Advances in Monomer Design and Polymerization Methods" (2016). LSU Doctoral Dissertations. 3676. https://digitalcommons.lsu.edu/gradschool_dissertations/3676 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Doctoral Dissertations by an authorized graduate school editor of LSU Digital Commons. For more information, please [email protected]. PEPTIDOMIMETIC POLYMERS: ADVANCES IN MONOMER DESIGN AND POLYMERIZATION METHODS A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Chemistry by Brandon Andrew Chan B.S., University of Michigan – Ann Arbor, 2009 August 2016 Victrix causa diis placuit, sed victa Catoni -Lucan, Pharsalia ii ACKNOWLEDGEMENTS First and foremost I would like to thank my advisor Prof. Donghui Zhang for her guidance, mentorship, and the plethora of opportunities to be at the cusp of cutting edge research throughout my time in graduate school. I also want to thank her for her encouragement and enthusiasm for each of the works contained in this document. Without it, I may have easily lost interest early in my graduate school career. I also want to thank her for supporting my plans to attend law school to become a patent attorney. On a related note, I want to acknowledge Prof. John Pojman who put me in contact with the right people to answer my questions about pursuing patent law. I also want to thank Profs. Paul Russo and David Spivak for their support and encouragement for both completion of my degree and for support of my law school plans. I want to also thank those in the LSU Department of Chemistry who have lent much support to the collection of data and assistance with experiments I never thought I would have ended up running. Specifically I want to acknowledge Connie David and Dr. Jeonhoon Lee for their assistance in ESI MS and MALDI TOF MS respectively, Dr. Rafael Cueto for teaching me everything I ever wanted to learn about polymer characterization and help with instrumentation, Drs. Thomas Weldeghiorghis and Fengli Zhang for their assistance in running NMR experiments, Dr. Frank Fronczek for his assistance in X-ray crystallography, and Prof. Evgueni Nesterov for the generous use of the UV-vis spectrometer. I final want to thank all Zhang group members for their help, support, encouragement, and listening to my rants. I would also like to thank my wife, Katie, for her patience, love, and support as we both go through the graduate school process together. iii TABLE OF CONTENTS ACKNOWLEDGEMENTS..........................................................................................iii LIST OF TABLES.......................................................................................................vii LIST OF FIGURES......................................................................................................ix LIST OF SCHEMES..................................................................................................xvii LIST OF ABBREVATIONS AND ACRONYMS...................................................... xx ABSTRACT..............................................................................................................xxiii CHAPTER I. INTRODUCTION TO PEPTIDOMIMETIC POLYMERS....................1 1.1 Overview of peptidomimetic polymers..............................................................1 1.2 Polypeptides…………………………………………………………………... 2 1.2.1 Solid phase synthesis of polypeptides…………………………………... 3 1.2.2 Polypeptide synthesis via the ring-opening polymerization of N- carboxyanhydride monomers............................................................................. 4 1.2.3 Post-polymerization modification of polypeptides................................. 23 1.3 Polypeptoids…..……………………………………………………………...29 1.3.1 Solid phase synthesis of polypeptoids……………………………….....31 1.3.2 Ring-opening polymerization of N-alkyl substituted glycine based NCA monomers to synthesize polypeptoids..............................................................32 1.4 Ring-opening polymerization of N-thiocarboxyanhydrosulfides.....................43 CHAPTER II. MULTIVALENT BINDING INTERACTIONS OF MANNOSE FUNCTIONALIZED GLYCOPOLYPEPTIDES WITH CONCANAVALIN A...................................................................................................................................46 2.1 Objectives.........................................................................................................46 2.2 Multivalent binding, glycopolymers, and glycopolypeptides.......................... 46 2.2.1 Multivalent carbohydrate-lectin interactions.......................................... 47 2.2.2 Glycopolymers........................................................................................ 49 2.2.3 Glycopolypeptides...................................................................................56 2.3 Results and discussion......................................................................................65 2.3.1 Synthesis and characterization of glycopolypeptides..............................65 2.3.2 Circular dichroism of glycopolypeptides................................................ 69 2.3.3 Binding studies of PPLG and PPDLG mannose with ConA ................. 71 2.3.3.1 Binding kinetic study.................................................................. 72 2.3.3.2 Binding stoichiometry from quantitative precipitation assay..... 75 2.3.4 Varying binding epitope density............................................................. 78 2.4 Dynamic light scattering of glycopolypeptides................................................82 2.5 Conclusions...................................................................................................... 84 2.6 Experimental.................................................................................................... 87 2.6.1 Instrumentation and general considerations............................................ 87 2.6.2 Synthesis of γ-propargyl-L-glutamate N-carboxyanhydride...................88 2.6.3 General procedure for the polymerization of γ-propargyl-L-glutamate N- carboxyanhydride............................................................................................. 89 2.6.4 Glycosylation of poly(γ-propargyl-L-glutamate) via CuAAC................90 iv 2.6.5 Circular dichroism...................................................................................91 2.6.6 Turbidity assay........................................................................................ 91 2.6.7 Quantitative precipitation assay.............................................................. 91 2.7 Supplemental data for Chapter II..................................................................... 92 CHAPTER III. 1,1,3,3-TETRAMETHYLGUANIDINE PROMOTED RING- OPENING POLYMERIZATION OF N-BUTYL N-CARBOXYANHYDRIDE USING ALCOHOL INITIATORS.............................................................................. 94 3.1 Objectives.........................................................................................................94 3.2 Introduction to organocatalysis in polymerization...........................................94 3.3 Results and discussion......................................................................................97 3.3.1 Initial results............................................................................................ 97 3.3.2 Competition with TMG initiation......................................................... 100 3.3.3 Demonstration of a living polymerization............................................ 105 3.3.4 Kinetic study of the polymerization...................................................... 106 3.3.5 Expanding the breadth of alcohol initiators and their dependence on sterics and electronics.....................................................................................109 3.3.6 Elucidation of an initiating pathway..................................................... 110 3.3.7 Macroinitiation of Bu-NCA with poly(ethylene glycol) monomethyl ether................................................................................................................123 3.4 Conclusions.................................................................................................... 124 3.5 Experimental.................................................................................................. 126 3.5.1 Instrumentation and general considerations.......................................... 126 3.5.2 Synthesis of N-butyl N-carboxyanhydride............................................ 128 3.5.3 General polymerization procedure........................................................ 129 3.5.4 General kinetics procedure....................................................................131 3.6 Supplemental data for Chapter III.................................................................
Load more

Recommended publications
  • REVIEW Signal Transduction, Cell Cycle Regulatory, and Anti
    Leukemia (1999) 13, 1109–1166 1999 Stockton Press All rights reserved 0887-6924/99 $12.00 http://www.stockton-press.co.uk/leu REVIEW Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs WL Blalock1, C Weinstein-Oppenheimer1,2, F Chang1, PE Hoyle1, X-Y Wang3, PA Algate4, RA Franklin1,5, SM Oberhaus1,5, LS Steelman1 and JA McCubrey1,5 1Department of Microbiology and Immunology, 5Leo Jenkins Cancer Center, East Carolina University School of Medicine Greenville, NC, USA; 2Escuela de Quı´mica y Farmacia, Facultad de Medicina, Universidad de Valparaiso, Valparaiso, Chile; 3Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, MN, USA; and 4Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Over the past decade, there has been an exponential increase growth factor), Flt-L (the ligand for the flt2/3 receptor), erythro- in our knowledge of how cytokines regulate signal transduc- poietin (EPO), and others affect the growth and differentiation tion, cell cycle progression, differentiation and apoptosis. Research has focused on different biochemical and genetic of these early hematopoietic precursor cells into cells of the 1–4 aspects of these processes. Initially, cytokines were identified myeloid, lymphoid and erythroid lineages (Table 1). This by clonogenic assays and purified by biochemical techniques. review will concentrate on IL-3 since much of the knowledge This soon led to the molecular cloning of the genes encoding of how cytokines affect cell growth, signal transduction, and the cytokines and their cognate receptors.
    [Show full text]
  • Effect of Soybean Oligopeptide on the Growth and Metabolism Of
    RSC Advances View Article Online PAPER View Journal | View Issue Effect of soybean oligopeptide on the growth and metabolism of Lactobacillus acidophilus JCM 1132 Cite this: RSC Adv., 2020, 10,16737 Wenhui Li, Yinxiao Zhang, He Li, * Chi Zhang, Jian Zhang, Jalal Uddin and Xinqi Liu* Soybean protein (Pro) and soybean oligopeptide (Pep) were subjected to simulated digestion in vitro to study the effect of Pep on the growth and metabolism of Lactobacillus acidophilus JCM 1132. First, the molecular weight distribution differences of samples before and after digestion were compared, and the samples were used to replace the nitrogen source components in the culture media. Then, the viable cell numbers, lactic acid and acetic acid content, differential metabolites, and metabolic pathways during the culturing process were measured. Results showed that the digested soybean oligopeptide (dPep) was less efficient than MRS medium in promoting the growth, but by increasing the content of the intermediates during the tricarboxylic acid (TCA) cycle, its metabolic capacity was significantly improved. Received 20th February 2020 Besides, due to the low molecular weight of dPep, it can be better transported and utilized. And dPep Creative Commons Attribution 3.0 Unported Licence. Accepted 20th April 2020 significantly strengthened the amino acid metabolism and weakened the glycerol phospholipid DOI: 10.1039/d0ra01632b metabolism, so the ability of dPep in promoting the growth and metabolism of Lactobacillus acidophilus rsc.li/rsc-advances JCM 1132 is higher than the digested soybean protein (dPro). 1. Introduction represent those that reach the intestine and directly acts on the intestinal ora aer digestion by the human body.13,14 Although Pro is a high-quality, nutritionally balanced plant Probiotics are mainly composed of Lactobacillus and Bido- protein displaying an excellent amino acid composition, it has bacterium.
    [Show full text]
  • Terminology of Bioanalytical Methods (IUPAC Recommendations 2018) Received November 21, 2016; Accepted February 1, 2018
    Pure Appl. Chem. 2018; 90(7): 1121–1198 IUPAC Recommendations Ján Labuda, Richard P. Bowater, Miroslav Fojta, Günter Gauglitz, Zdeněk Glatz, Ivan Hapala, Jan Havliš, Ferenc Kilar, Aniko Kilar, Lenka Malinovská, Heli M. M. Sirén, Petr Skládal, Federico Torta, Martin Valachovič, Michaela Wimmerová, Zbyněk Zdráhal and David Brynn Hibbert* Terminology of bioanalytical methods (IUPAC Recommendations 2018) https://doi.org/10.1515/pac-2016-1120 Received November 21, 2016; accepted February 1, 2018 Abstract: Recommendations are given concerning the terminology of methods of bioanalytical chemistry. With respect to dynamic development particularly in the analysis and investigation of biomacromolecules, terms related to bioanalytical samples, enzymatic methods, immunoanalytical methods, methods used in genomics and nucleic acid analysis, proteomics, metabolomics, glycomics, lipidomics, and biomolecules interaction studies are introduced. Keywords: bioanalytical samples; biomolecule interaction studies; enzymatic methods; genomics; glycom- ics; immunoanalytical methods; lipidomics; metabolomics; nucleic acid analysis; proteomics. CONTENTS 1. PREFACE �������������������������������������������������������������������������������������������������������������������������������������� 1122 2. INTRODUCTION ��������������������������������������������������������������������������������������������������������������������������� 1122 3. BIOANALYTICAL SAMPLES ����������������������������������������������������������������������������������������������������������
    [Show full text]
  • BCL-2 in the Crosshairs: Tipping the Balance of Life and Death
    Cell Death and Differentiation (2006) 13, 1339–1350 & 2006 Nature Publishing Group All rights reserved 1350-9047/06 $30.00 www.nature.com/cdd Review BCL-2 in the crosshairs: tipping the balance of life and death LD Walensky*,1,2,3 the founding member of a family of proteins that regulate cell death.1–3 Gene rearrangement places BCL-2 under the 1 Departments of Pediatric Oncology and Cancer Biology, Dana-Farber Cancer transcriptional control of the immunoglobulin heavy chain Institute, Harvard Medical School, Boston, MA 02115, USA locus, resulting in high-level BCL-2 expression and pathologic 2 Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Harvard cell survival.4,5 The oncogenic activity of BCL-2 derives from Medical School, Boston, MA 02115, USA 3 Division of Hematology/Oncology, Children’s Hospital Boston, Harvard Medical its ability to block cell death following a wide variety of 6–8 School, Boston, MA 02115, USA stimuli. Transgenic mice bearing a BCL-2-Ig minigene * Corresponding author: LD Walensky, Department of Pediatric Oncology, initially displayed a polyclonal follicular lymphoproliferation Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. that selectively expanded a small resting IgM/IgD B-cell Tel: þ 617-632-6307; Fax: þ 617-632-6401; population.4,9 These recirculating B cells accumulated be- E-mail: [email protected] cause of an extended survival rather than increased prolifera- Received 21.3.06; revised 04.5.06; accepted 09.5.06; published online 09.6.06 tion. Despite a fourfold increase in resting B cell counts, Edited by C Borner BCL-2-Ig mice were initially quite healthy.
    [Show full text]
  • Cancer Chemotherapy with Peptides and Peptidomimetics Drug and Peptide Based-Vaccines
    International Research Journal of Pharmacy and Medical Sciences ISSN (Online): 2581-3277 Cancer Chemotherapy with Peptides and Peptidomimetics Drug and Peptide Based-Vaccines Jeevan R. Rajguru*1, Sonali A. Nagare2, Ashish A. Gawai3, Amol G. Jadhao4, Mrunal K. Shirsat5 1, 4Master of Pharmacy in Pharmaceutics at Anuradha College of Pharmacy, Chikhli, Dist-Buldana M.S, India 2Department of Pharmaceutical Chemistry Loknete Shri Dadapatil Pharate College of pharmacy, Mandavgan Pharata, Shirur Pune, M.S, India 3Associate Professor, Department of Pharmaceutical Chemistry at Anuradha College of pharmacy, Chikhli, Dist- Buldana M.S, India 5Department of Pharmacognosy and Principal of Loknete Shri Dadapatil Pharate College of pharmacy, Mandavgan Pharata, Shirur Pune, M.S, India Corresponding Author Email ID: jeevanrajguru 97 @ gmail. com Co-Author Email ID: sonalinagare 93 @ gmail. com Abstract— A summary of the current status of the application of peptidomimetics in cancer therapeutics as an alternative to peptide drugs is provided. Only compounds that are used in therapy or at least under clinical trials are discussed, using inhibitors of farnesyltransferase, proteasome and matrix metalloproteinases as examples. The design and synthesis of peptidomimetics are most important because of the dominant position peptide and protein-protein interactions play in molecular recognition and signalling, especially in living systems. The design of peptidomimetics can be viewed from several different perspectives and peptidomimetics can be categorized in a number of different ways. Study of the vast literature would suggest that medicinal and organic chemists, who deal with peptide mimics, utilize these methods in many different ways. Conventional methods used to treat cancer, from non-specific chemotherapy to modern molecularly targeted drugs have generated limited results due to the complexity of the disease as well as lack of molecular classes that can be developed into treatments rapidly, easily and economically.
    [Show full text]
  • Applications of Oligopeptide-Functionalized
    APPLICATIONS OF OLIGOPEPTIDE-FUNCTIONALIZED SURFACES AND MICROPARTICLES IN LIQUID CRYSTALS- BASED ASSAYS ONG LIAN HAO (B.ENG. (HONS.), NANYANG TECHNOLOGICAL UNIVERSITY) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMICAL AND BIOMOLECULAR ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2016 DECLARATION I hereby declare that this thesis is my original work and it has been written by me in its entirety. I have duly acknowledged all the sources of information which have been used in the thesis. This thesis has also not been submitted for any degree in any university previously. Ong Lian Hao 10 September 2016 i ACKNOWLEDGEMENTS First of all, I am utmost grateful for the opportunity presented by my advisor, Dr. Yang Kun-Lin, to complete this thesis under his guidance. His insightful perspectives and open-door policy provided a conducive environment for me to develop and hone my research skills and ideologies. I am also thankful for the engaging, and more importantly enlightening discussions with our group members, and they include Dr. Liu Fengli, Dr. Chen Chih-Hsin, Dr. Ding Xiaokang, Ms. Liu Yanyang, Ms. Nguyen Le Truc and Dr. Arumugam Kamayan Rajagopalan G. I am also fortunate to receive guidance and advice from Dr. Saif Khan and his group members during our regular intergroup sharing sessions. I would also like to thank the friendly laboratory staff for their assistance in the procurement and operation of equipment, and they include Mr. Boey Kok Hong, Ms. Lee Chai Keng, Mr. Liu Zhicheng, Ms. Lim Kwee Mei, Dr. Yuan Ze Liang and Dr. Yang Liming. Finally, I am grateful to my parents and parents-in-law for their support.
    [Show full text]
  • Leveraging the Bcl-2 Interactome to Kill Cancer Cells—
    Author Manuscript Published OnlineFirst on April 2, 2015; DOI: 10.1158/1078-0432.CCR-14-0959 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Molecular Pathways: Leveraging the Bcl-2 Interactome to Kill Cancer Cells— Mitochondrial Outer Membrane Permeabilization and Beyond Hetal Brahmbhatt1,2, Sina Oppermann2, Elizabeth J. Osterlund2,3, Brian Leber4, and David W. Andrews1,2,3 1Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. 2Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada. 3Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada. 4Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Corresponding Author: David W. Andrews, Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada. M4N 3M5. Phone: 416-480-5120; Fax: 416-480-4375; E-mail: [email protected] Running Title: Bcl-2 Proteins as Chemotherapy Targets Disclosure of Potential Conflicts of Interest B. Leber reports receiving speakers bureau honoraria from AMGEN Canada, Bristol-Myers Squibb Canada, Celgene Canada, Novartis Canada, and Pfizer Canada. No potential conflicts of interest were disclosed by the other authors. Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 2, 2015; DOI: 10.1158/1078-0432.CCR-14-0959 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT The inhibition of apoptosis enables the survival and proliferation of tumors and contributes to resistance to conventional chemotherapy agents and is therefore a very promising avenue for the development of new agents that will enhance current cancer therapies.
    [Show full text]
  • Peptidomimetic Blockade of MYB in Acute Myeloid Leukemia
    bioRxiv preprint doi: https://doi.org/10.1101/222620; this version posted November 20, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Peptidomimetic blockade of MYB in acute myeloid leukemia 2 3 4 Kavitha Ramaswamy1,2, Lauren Forbes1,7, Gerard Minuesa1, Tatyana Gindin3, Fiona Brown1, 5 Michael Kharas1, Andrei Krivtsov4,6, Scott Armstrong2,4,6, Eric Still1, Elisa de Stanchina5, Birgit 6 Knoechel6, Richard Koche4, Alex Kentsis1,2,7* 7 8 9 1 Molecular Pharmacology Program, Sloan Kettering Institute, New York, NY, USA. 10 2 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 11 3 Department of Pathology and Cell Biology, Columbia University Medical Center and New York 12 Presbyterian Hospital, New York, NY, USA. 13 4 Center for Epigenetics Research, Sloan Kettering Institute, New York, NY, USA. 14 5 Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, 15 USA. 16 6 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 17 7 Weill Cornell Medical College, Cornell University, New York, NY, USA. 18 19 * Correspondence should be addressed to A.K. ([email protected]). 1 bioRxiv preprint doi: https://doi.org/10.1101/222620; this version posted November 20, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 20 ABSTRACT 21 22 Aberrant gene expression is a hallmark of acute leukemias. However, therapeutic strategies for 23 its blockade are generally lacking, largely due to the pharmacologic challenges of drugging 24 transcription factors.
    [Show full text]
  • Synthesis of Equimolar Multiple Oligomer Mixtures
    Europaisches Patentamt (19) European Patent Office Office europeenpeen des brevets EP 0 558 671 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) intci.6: C07K1/04, C07K7/06, of the grant of the patent: A61 K 38/00, G01 N 33/53 27.01.1999 Bulletin 1999/04 (86) International application number: (21) Application number: 92902209.3 PCT/US91/08694 Date of 20.11.1991 (22) filing: (87) International publication number: WO 92/09300 (11.06.1992 Gazette 1992/13) (54) SYNTHESIS OF EQUIMOLAR MULTIPLE OLIGOMER MIXTURES, ESPECIALLY OF OLIGOPEPTIDE MIXTURES SYNTHESE AQUIMOLARER MISCHUNGEN VIELZAHLIGER OLIGOMERE, SPEZIELL OLIGOPEPTIDMISCHUNGEN SYNTHESE DE MELANGES OLIGOMERES MULTIPLES EQUIMOLAIRES, NOTAMMENT DE MELANGES D'OLIGOPEPTIDES (84) Designated Contracting States: (56) References cited: AT BE CH DE DK ES FR GB GR IT LI LU NL SE US-A- 4 631 211 US-A-5 010 175 (30) Priority: 21.11.1990 US 617023 BANBURY REP. vol. 29, 1988, pages 151-161 16.05.1991 US 701658 HOUGHTEN, R.A. 'Exact amino acid involvement 19.11.1991 US 797551 in the interactions of peptide antigens with monoclonal antibodies' (43) Date of publication of application: PROTIDES BIOL. FLUIDS vol. 34, 1986, pages 19 08.09.1993 Bulletin 1993/36 - 22 HOUGHTEN, R.A. 'Facile determination of exact amino acid involvement in peptide (73) Proprietor: ITEREX PHARMACEUTICALS LTD. antigen/monoclonal antibody interactions' PARTNERSHIP J. IMMUNOL, vol. 144, no. 3, 1 February 1990, San Diego, C A 92121 (US) pages 976 - 983 APPEL J.R. ET AL. 'Elucidation of discontinuous linear determinants in (72) Inventors: peptides' • HOUGHTEN, Richard, A.
    [Show full text]
  • Amide Bond Formation in Nonribosomal Peptide Synthesis
    Amide Bond Formation in Nonribosomal Peptide Synthesis: The Formylation and Condensation Domains Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) dem Fachbereich Chemie der Philipps-Universität Marburg vorgelegt von Georg Schönafinger aus München Marburg/Lahn 2007 Vom Fachbereich Chemie der Philipps-Universität Marburg als Dissertation am _______________ angenommen. Erstgutachter : Prof. Dr. M. A. Marahiel (Philipps-Universität, Marburg) Zweitgutachter : Prof. Dr. L.-O. Essen (Philipps-Universität, Marburg) Tag der Disputation: 20. Dezember 2007 2 The majority of the work presented here has been published: Samel, S.A.†, Schoenafinger, G. †, Knappe, T.A., Marahiel, M.A., Essen, L.O. 2007. Structural and functional insights into a peptide bond-forming bidomain from a nonribosomal peptide synthetase. Structure 15(7): 781-92. † equal contribution Schoenafinger, G., Schracke, N., Linne, U., Marahiel, M.A. 2006. Formylation domain: an essential modifying enzyme for the nonribosomal biosynthesis of linear gramicidin. J Am Chem Soc. 128(23): 7406-7. Schoenafinger, G., Marahiel, M.A. accepted 2007. Nonribosomal Peptides. Wiley Encyclopaedia of Chemical Biology. In press. 3 To Anke 4 Summary Nonribosomal peptides are of outstanding pharmacological interest, since many representatives of this highly diverse class of natural products exhibit therapeutically important activities, such as antibacterial, antitumor and immunosuppressive properties. Understanding their biosynthesis performed by multimodular mega-enzymes, the nonribosomal peptide synthetases (NRPSs), is one of the key determinants in order to be able to reprogram these machineries for the production of novel therapeutics. The central structural motif of all peptides is the peptide (or amide) bond. In this work, two different amide bond forming catalytic entities from NRPSs were studied: The condensation (C) and formylation (F) domains.
    [Show full text]
  • A Simplified Reconstitution of Mrna-Directed Peptide Synthesis: Activity of the Epsilon Enhancer and an Unnatural Amino Acid1
    Analytical Biochemistry 297, 60–70 (2001) doi:10.1006/abio.2001.5329, available online at http://www.idealibrary.com on A Simplified Reconstitution of mRNA-Directed Peptide Synthesis: Activity of the Epsilon Enhancer and an Unnatural Amino Acid1 Anthony C. Forster,*,2 Herbert Weissbach,† and Stephen C. Blacklow*,2 *Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115; and †Center for Molecular Biology and Biotechnology, Florida Atlantic University, 777 Glades Road, Boca Raton, Florida 33431 Received March 13, 2001; published online August 30, 2001 Key Words: translation; reconstitution; E. coli; ribo- The study of the early events in translation would some; initiation factor; elongation factor; tRNA; en- be greatly facilitated by reconstitution with easily hancer; epsilon; peptide; unnatural amino acid; biotin. purified components. Here, Escherichia coli oli- gopeptide synthesis has been reconstituted using five purified recombinant His-tagged E. coli initia- tion and elongation factors. Highly purified ribo- The initiation of translation is a major control point somes are required to yield products with strong in gene expression and is the target of a number of dependencies on the translation factors. Based on cytotoxic agents (1). Initiation is less well understood HPLC separation of radiolabeled translation prod- than elongation and termination in eubacteria (2–4), ucts from an mRNA encoding a tetrapeptide, approx- and initiation is much more complex in eukaryotes (5). imately 80% of peptide products are full length, and It therefore seems likely that the study of the simpler the remaining 20% are the dipeptide and tripeptide eubacterial initiation process may be helpful both in products resulting from pausing or premature ter- the elucidation of general mechanistic principles em- mination.
    [Show full text]
  • A Global Review on Short Peptides: Frontiers and Perspectives †
    molecules Review A Global Review on Short Peptides: Frontiers and Perspectives † Vasso Apostolopoulos 1 , Joanna Bojarska 2,* , Tsun-Thai Chai 3 , Sherif Elnagdy 4 , Krzysztof Kaczmarek 5 , John Matsoukas 1,6,7, Roger New 8,9, Keykavous Parang 10 , Octavio Paredes Lopez 11 , Hamideh Parhiz 12, Conrad O. Perera 13, Monica Pickholz 14,15, Milan Remko 16, Michele Saviano 17, Mariusz Skwarczynski 18, Yefeng Tang 19, Wojciech M. Wolf 2,*, Taku Yoshiya 20 , Janusz Zabrocki 5, Piotr Zielenkiewicz 21,22 , Maha AlKhazindar 4 , Vanessa Barriga 1, Konstantinos Kelaidonis 6, Elham Mousavinezhad Sarasia 9 and Istvan Toth 18,23,24 1 Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia; [email protected] (V.A.); [email protected] (J.M.); [email protected] (V.B.) 2 Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego˙ 116, 90-924 Lodz, Poland 3 Department of Chemical Science, Faculty of Science, Universiti Tunku Abdul Rahman, Kampar 31900, Malaysia; [email protected] 4 Botany and Microbiology Department, Faculty of Science, Cairo University, Gamaa St., Giza 12613, Egypt; [email protected] (S.E.); [email protected] (M.A.) 5 Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego˙ 116, 90-924 Lodz, Poland; [email protected] (K.K.); [email protected] (J.Z.) 6 NewDrug, Patras Science Park, 26500 Patras, Greece; [email protected] 7 Department of Physiology and Pharmacology,
    [Show full text]