Development and Evaluation of Novel Hydrocarbon Stapled Peptidomimetics with Future Application to Bionic Proteins
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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. -
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. -
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. -
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. -
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. -
Stapled Α−Helical Peptide Drug Development: a Potent PNAS PLUS Dual Inhibitor of MDM2 and MDMX for P53-Dependent Cancer Therapy
Stapled α−helical peptide drug development: A potent PNAS PLUS dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy Yong S. Changa,1,2, Bradford Gravesb,1, Vincent Guerlavaisa, Christian Tovarb, Kathryn Packmanb, Kwong-Him Tob, Karen A. Olsona, Kamala Kesavana, Pranoti Gangurdea, Aditi Mukherjeea, Theresa Bakera, Krzysztof Darlaka, Carl Elkina, Zoran Filipovicb, Farooq Z. Qureshib, Hongliang Caia, Pamela Berryb, Eric Feyfanta, Xiangguo E. Shia, James Horsticka, D. Allen Annisa, Anthony M. Manninga, Nader Fotouhib, Huw Nasha, Lyubomir T. Vassilevb,2, and Tomi K. Sawyera,2 aAileron Therapeutics, Inc., Cambridge, MA 02139; and bRoche Research Center, Hoffmann-La Roche, Inc., Nutley, NJ 07110 Edited* by Robert H. Grubbs, California Institute of Technology, Pasadena, CA, and approved July 12, 2013 (received for review February 17, 2013) Stapled α−helical peptides have emerged as a promising new mo- each unable to compensate for the loss of the other, and they dality for a wide range of therapeutic targets. Here, we report regulate nonoverlapping functions of p53 (4, 6). a potent and selective dual inhibitor of MDM2 and MDMX, The first potent and selective small-molecule inhibitors of the ATSP-7041, which effectively activates the p53 pathway in tumors p53–MDM2 interaction, the Nutlins, provided proof of concept in vitro and in vivo. Specifically, ATSP-7041 binds both MDM2 and that restoration of p53 activity is feasible and may have appli- MDMX with nanomolar affinities, shows submicromolar cellular cation in cancer therapy (11, 12). Although three different activities in cancer cell lines in the presence of serum, and dem- classes of small-molecule MDM2 antagonists are currently under onstrates highly specific, on-target mechanism of action. -
A Short Double-Stapled Peptide Inhibits Respiratory Syncytial Virus Entry and Spreading
A short double-stapled peptide inhibits respiratory syncytial virus entry and spreading Vanessa Gaillard, Marie Galloux, Dominique Garcin, Jean Francois Eleouet, Ronan Le Goffic, Thibaut Larcher, Marie-Anne Rameix-Welti, Abdelhak Boukadiri, Julien Heritier, Jean-Manuel Segura, et al. To cite this version: Vanessa Gaillard, Marie Galloux, Dominique Garcin, Jean Francois Eleouet, Ronan Le Goffic, et al.. A short double-stapled peptide inhibits respiratory syncytial virus entry and spreading. Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2017, 61 (4), 10.1128/AAC.02241-16. hal-01605887 HAL Id: hal-01605887 https://hal.archives-ouvertes.fr/hal-01605887 Submitted on 26 May 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License ANTIVIRAL AGENTS crossm A Short Double-Stapled Peptide Inhibits Respiratory Syncytial Virus Entry and Spreading Vanessa Gaillard,a Marie Galloux,b Dominique Garcin,c Jean-François Eléouët,b b d e,f Ronan Le Goffic, Thibaut Larcher, -
Designing Peptidomimetics
CORE Metadata, citation and similar papers at core.ac.uk Provided by UPCommons. Portal del coneixement obert de la UPC DESIGNING PEPTIDOMIMETICS Juan J. Perez Dept. of Chemical Engineering ETS d’Enginyeria Industrial Av. Diagonal, 647 08028 Barcelona, Spain 1 Abstract The concept of a peptidomimetic was coined about forty years ago. Since then, an enormous effort and interest has been devoted to mimic the properties of peptides with small molecules or pseudopeptides. The present report aims to review different approaches described in the past to succeed in this goal. Basically, there are two different approaches to design peptidomimetics: a medicinal chemistry approach, where parts of the peptide are successively replaced by non-peptide moieties until getting a non-peptide molecule and a biophysical approach, where a hypothesis of the bioactive form of the peptide is sketched and peptidomimetics are designed based on hanging the appropriate chemical moieties on diverse scaffolds. Although both approaches have been used in the past, the former has been more widely used to design peptidomimetics of secretory peptides, whereas the latter is nowadays getting momentum with the recent interest in designing protein-protein interaction inhibitors. The present report summarizes the relevance of the information gathered from structure-activity studies, together with a short review on the strategies used to design new peptide analogs and surrogates. In a following section there is a short discussion on the characterization of the bioactive conformation of a peptide, to continue describing the process of designing conformationally constrained analogs producing first and second generation peptidomimetics. Finally, there is a section devoted to review the use of organic scaffolds to design peptidomimetics based on the information available on the bioactive conformation of the peptide. -
ASTX660, a Novel Non-Peptidomimetic Antagonist of Ciap1/2 and XIAP, Potently Induces Tnfa-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth George A
Published OnlineFirst April 25, 2018; DOI: 10.1158/1535-7163.MCT-17-0848 Small Molecule Therapeutics Molecular Cancer Therapeutics ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNFa-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth George A. Ward, Edward J. Lewis, Jong Sook Ahn, Christopher N. Johnson, John F. Lyons, Vanessa Martins, Joanne M. Munck, Sharna J. Rich, Tomoko Smyth, Neil T. Thompson, Pamela A. Williams, Nicola E. Wilsher, Nicola G. Wallis, and Gianni Chessari Abstract Because of their roles in the evasion of apoptosis, inhibitor of antagonism of XIAP was demonstrated by measuring its dis- apoptosis proteins (IAP) are considered attractive targets for placement from caspase-9 or SMAC. Compound-induced pro- anticancer therapy. Antagonists of these proteins have the teasomal degradation of cIAP1 and 2, resulting in downstream potential to switch prosurvival signaling pathways in cancer effects of NIK stabilization and activation of noncanonical cells toward cell death. Various SMAC-peptidomimetics with NF-kB signaling, demonstrated cIAP1/2 antagonism. Treatment inherent cIAP selectivity have been tested clinically and dem- withASTX660ledtoTNFa-dependent induction of apoptosis onstrated minimal single-agent efficacy. ASTX660 is a potent, in various cancer cell lines in vitro, whereas dosing in mice non-peptidomimetic antagonist of cIAP1/2 and XIAP, discov- bearing breast and melanoma tumor xenografts inhibited ered using fragment-based drug design. The antagonism of tumor growth. ASTX660 is currently being tested in a phase XIAP and cIAP1 by ASTX660 was demonstrated on purified I–II clinical trial (NCT02503423), and we propose that its proteins, cells, and in vivo in xenograft models. -
Stapled Peptides—A Useful Improvement for Peptide-Based Drugs
molecules Review Stapled Peptides—A Useful Improvement for Peptide-Based Drugs Mattia Moiola, Misal G. Memeo and Paolo Quadrelli * Department of Chemistry, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy; [email protected] (M.M.); [email protected] (M.G.M.) * Correspondence: [email protected]; Tel.: +39-0382-987315 Received: 30 July 2019; Accepted: 1 October 2019; Published: 10 October 2019 Abstract: Peptide-based drugs, despite being relegated as niche pharmaceuticals for years, are now capturing more and more attention from the scientific community. The main problem for these kinds of pharmacological compounds was the low degree of cellular uptake, which relegates the application of peptide-drugs to extracellular targets. In recent years, many new techniques have been developed in order to bypass the intrinsic problem of this kind of pharmaceuticals. One of these features is the use of stapled peptides. Stapled peptides consist of peptide chains that bring an external brace that force the peptide structure into an a-helical one. The cross-link is obtained by the linkage of the side chains of opportune-modified amino acids posed at the right distance inside the peptide chain. In this account, we report the main stapling methodologies currently employed or under development and the synthetic pathways involved in the amino acid modifications. Moreover, we report the results of two comparative studies upon different kinds of stapled-peptides, evaluating the properties given from each typology of staple to the target peptide and discussing the best choices for the use of this feature in peptide-drug synthesis. Keywords: stapled peptide; structurally constrained peptide; cellular uptake; helicity; peptide drugs 1. -
Phase I Trial of the Matrix Metalloproteinase Inhibitor Marimastat Combined with Carboplatin and Paclitaxel in Patients with Advanced Non−Small Cell Lung Cancer
Cancer Therapy: Clinical PhaseITrialoftheMatrixMetalloproteinaseInhibitorMarimastat Combined with Carboplatin and Paclitaxel in Patients with Advanced Non ^ Small Cell Lung Cancer John R. Goffin,1, 2 Ian C. Anderson,1,4 Jeffrey G. Supko,3 Joseph Paul Eder, Jr.,1 Geoffrey I. Shapiro,1 Thomas J. Lynch,3 Margaret Shipp,1 Bruce E. Johnson,1 and Arthur T. Skarin 1 Abstract Purpose: Marimastat is an orally bioavailable inhibitor of matrix metalloproteinases. A phase I study was initiated to determine whether conventional doses of carboplatin and paclitaxel are tolerated when combined with marimastat and to assess the influence of marimastat on paclitaxel pharmacokinetics. Experimental Design: Three dose levels were evaluated. Marimastat (10 or 20 mg oral admin- istration b.i.d.) was administered continuously with paclitaxel (175 or 200 mg/m2 as a 3-hour i.v. infusion) and carboplatin (at a dose providing an area under the free drug plasma concentration- time curve of 7 mg min/mL) administered each 3 weeks. Toxicity and response were evaluated throughout the intended four cycles of combined therapy. The plasma pharmacokinetics of pacli- taxel was determinedin each patient both without concurrent marimastat and after receiving mari- mastat for1week. Results: Twenty-two chemotherapy-naive patients with stage IIIb (27%) or stage IV (73%) non ^ small cell lung cancer were enrolled. Their median age was 56 years (range, 39-73 years), 50% were female, and their performance status (Eastern Cooperative Oncology Group) ranged from0 to 2. Treatmentwas well tolerated, as 18 (82%) of the patients completed all four cycles of chemotherapy without dose-limiting toxicity. Grade 2 musculoskeletal toxicities were reported in 3 of 12 patients receiving marimastat (20 mg b.i.d.). -
Quantitative Mapping of Protein-Peptide Affinity
bioRxiv preprint doi: https://doi.org/10.1101/306779; this version posted July 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Quantitative mapping of protein-peptide affinity landscapes using spectrally encoded beads Huy Nguyen1, Jagoree Roy2,*, Björn Harink1,*, Nikhil Damle2,*, Brian Baxter3, Kara Brower5, Tanja Kortemme6,7, Kurt Thorn4, Martha Cyert2, and Polly Fordyce1,5,7,8 1 Department of Genetics, Stanford University, Stanford, CA 94305 2 Department of Biology, Stanford University, Stanford, CA 94305 3 Department of Biochemistry & Biophysics, University of California San Francisco, San Francisco, CA 94158 4 Zymergen, Inc., San Francisco, CA 5 Department of Bioengineering, Stanford University, Stanford, CA 94305 6 Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158 7 Chan Zuckerberg Biohub, San Francisco, CA 94158 8 ChEM-H Institute, Stanford University, Stanford, CA 94305 *These authors contributed equally to this work. Abstract Transient, regulated binding of globular protein domains to Short Linear Motifs (SLiMs) in disordered regions of other proteins drives cellular signaling. Mapping the energy landscapes of these interactions is essential for deciphering and therapeutically perturbing signaling networks, but is challenging due to their weak affinities. We present a powerful technology, MRBLE-pep, that simultaneously quantifies protein binding to a library of peptides directly synthesized on beads containing unique spectral codes. Using computational modeling and MRBLE-pep, we systematically probe binding of calcineurin (CN), a conserved protein phosphatase essential for the immune response and target of immunosuppressants, to the PxIxIT SLiM.