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Table 1. Inhibitory activity of the peptoid libraryNameStructure%Inhibition(100 µM)%Inhibition(5 µM)PTR6154 H-Arg-Pro-Arg-Nva-Tyr-Dap-Hol-NH 2 99 ± 1 87 ± 2Peptomer1aHN CH 2(CH 2 ) 3NHCNH 2NHCOPro Arg Nva Tyr Dap Hol NH 295 ± 1 32 ± 4Peptomer3aHArg Pro N CH 2(CH 2 ) 3NHCNHCONva Tyr Dap Hol NH 230 ± 4 N.D.NH 2Peptomer4aHArg Pro Arg N CH 2 C Tyr Dap Hol NH 2(CH 2 ) 2 OCH 316 ± 4 N.D.Peptomer5aHArg Pro Arg Nva NCH 2CH 2C Dap Hol NH 2O85 ± 5 23 ± 4Peptomer7a #OHH Arg Pro Arg Nva Tyr Dap N CH 2 C NH 2CH 2 OCH CH 3CH 2CH 339 ± 1 N.D.PKB/Akt inhibition was determined according to radioactive kinase assay. Inhibition atthe concentration of inhibitor indicated in parenthesis is shown as the percent of reductionin PKB/Akt activity (0% inhibition = activity in the absence of inhibitor). % inhibition at 5µM was determined only for inhibitors that showed over 80% inhibition at 100 µM. N.I. =no inhibition. N.D. = not determined. # A HoIle peptomer building unit was preparedinstead of a Hol peptomer building unit.conformational freedom is vital for proper substrate-enzyme complementarity fit andtherefore, any local constraints induced by steric effects reduce efficacy significantly.AcknowledgmentsA.L. was supported by grants from The European Commission (Prokinase Consortium), the ProstateCancer Foundation (USA) and the Goldhirsh Foundation (USA).References1. Litman, P., et al. Biochemistry 46, 4716-4724 (2007).2. Meyer, J.P., Davis, P., et al. J. Med. Chem. 38, 3462 (1995).3. Nuss, J.M., et al. Pure Appl. Chem. 69, 447 (1997).4. Park, M.-S., Oh, H.-S., Cho, H., Lee, K.-H. Tetrahedron Lett. 48, 1053 (2007).5. Tal-Gan, Y., Freeman, N.S., Klein, S., Levitzki, A., Gilon, C. Bioorg. Med. Chem. 18, 2976-2985(2010).227
Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Application of Fragment Based Drug Design for the Discoveryof Peptidomimetic as Inhibitors of CyclophilinsLionel Colliandre 1 , Abdelhakim Ahmed-Belkacem 2 ,Jean-Michel Pawlotsly 2 , and Jean-François Guichou 11 Centre de Biochimie Structurale, UMR5048, UM1, CNRS, Inserm, 34090, Montpellier,France; 2 IMRB, Inserm U955, Equipe 18, Hôpital Henri Mondor, 94010, Créteil, FranceIntroductionOngoing Hepatitis C virus (HCV) is a major causative agent of chronic hepatitis, cirrhosis,and hepatocellular carcinoma. Approximately 200 million individuals are infectedworldwide and HCV infection causes approximately 280,000 deaths per year. The currentstandard treatment for chronic hepatitis C is based on the use of pegylated interferon(IFN- ) in combination with ribavirin for up to one year. However, only up to 50% ofpatient with HCV genotype 1 infection can eradicate infection upon therapy. Moreover,both IFN- and ribavirin are associated with adverse effects. Therefore, more efficient andbetter tolerated therapies are needed for hepatitis C. Current HCV “Drug Discovery” effortsfocus primarily on developing molecules that specifically inhibit the function of two viralenzymes: the NS3-4A serine protease and the NS5B RNA-dependant polymerase, both ofwhich are essential for viral replication. However, due to the high genetic variability of thevirus, amino acid substitutions that confer drug resistance are likely to emerge duringtreatment with specific inhibitors of the HCV protease or polymerase. Viruses depend onhost-derived factors that are required for viral replication and may be less prone to thedevelopment of drug resistance. Cyclophilins are cellular factors that were initiallyidentified as having high affinity for cyclosporine A (CsA), an immunosuppressive agent.Cyclophilins form a family of peptidyl-prolyl isomerases that catalyze the cis-transinterconversion of amino-terminal peptide bonds to proline residues, facilitating changes inprotein conformation. Some authors have recently reported the involvement of CypA and Bin HCV genome replication and proposed a model for the molecular mechanism, whereCyp’s would interact with NS5B and promote its RNA binding affinity. The Cyp’srepresents an interesting target for the development of new antiviral strategies targetingHCV replication without targeting viral enzymes. The application of Fragment Based DrugDesign to Cyclophilins for the design and synthesis of peptidomimetic as inhibitors forthese enzymes was performed.Results and DiscussionSeveral rounds of virtual screening were used to focus on fragments to be screened byNMR and X-Ray crystallography against CypD. Virtual screening was performed onfiltered lists from the ZINC Database. Examples of the properties used for filtering weremolecular weight (
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Peptides 2010Tales of PeptidesProce
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Peptides 2010Tales of PeptidesProce
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IntroductionWe had the distinct hon
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Scientific programIn planning the 3
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31 st EUROPEAN PEPTIDE SYMPOSIUMSep
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published by John Wiley & Sons as a
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The Josef Rudinger AwardThis award
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Young Investigators' SymposiumThe y
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xxiv
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Design of Peptidyl-Inhibitors for G
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Synthetic Antifreeze Glycopeptide A
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Synthesis and Oxidative Folding of
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Convergent Syntheses of Huprp106-12
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Bactericidal Activity of Small Beta
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Bradykinin Analogues Acylated on Th
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Antimicrobial Activity of Small 3-(
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Interaction of Curcumin with A-Synu
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Fluorescent and Luminescent Fusion
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Cellular Expression of the Human An
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2D IR Spectroscopy of Oligopeptides
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large, non-redundant subset of prot
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The aberrantly glucosylated peptide
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Table 1. Proline cis/trans ratios o
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Table 1. Yields, UV-vis absorption
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Table 1. Purity of the targeted tri
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processes are blocked. Interestingl
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(tb4 n ,1 m )MTII(tb1 n ,4 m )MTIIF
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Fig. 2. a) Part of the 400 MHz HR-M
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Once printed, the amino acid partic
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A) PSA, few seconds73B) PSA, 45 min
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short β strands. In contrast, nume
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neg. control Cs9-Rhd MM-218Fig. 2.
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Table 1. The general structure of t
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% ID in the liver 1 h p.i.100908070
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Peptidyl phosphoranes were first re
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obtained from the same sardines and
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MccJ25 variants were produced by si
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Fig. 2. Proposed signaling mechanis
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Table 1. mCD4-HS12 antiviral activi
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Proceedings of the 31 st European P
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Subject index(S)-2-(1-adamantyl)gly
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chip 18chiral triazine condensing r
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heat stress 348helical conformation
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O-acyl isopeptide method 112obesity
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SH2-ligands 210short collagen-relat
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Author indexAboye, Teshome Leta 142
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Chi, Hongfang 480Chiche, Laurent 6C
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Geronikaki, Athina 444Gessmann, Ren
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Kostova, Kalina 528Kotzia, Georgia
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Nagata, Koji 162Nagayev, Igor Yu. 5
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Salvarese, Nicola 518Sammet, Benedi
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Vauquelin, Georges 138Veiga, Ana Sa
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