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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 (