title: Molecular mechanism by which a potent hepatitis C virus NS3-NS4A protease inhibitor overcomes emergence of resistance.
abstract: Although optimizing the resistance profile of an inhibitor can be challenging, it is potentially important for improving the long term effectiveness of antiviral therapy. This work describes our rational approach toward the identification of a macrocyclic acylsulfonamide that is a potent inhibitor of the NS3-NS4A proteases of all hepatitis C virus genotypes and of a panel of genotype 1-resistant variants. The enhanced potency of this compound versus variants D168V and R155K facilitated x-ray determination of the inhibitor-variant complexes. In turn, these structural studies revealed a complex molecular basis of resistance and rationalized how such compounds are able to circumvent these mechanisms.
authors.affiliation: Boehringer Ingelheim (Canada) Limited, Research and Development, Laval, Quebec H7S 2G5, Canada. RESGeneral.lav@boehringer-ingelheim.com
authors.forename: Jeff A
authors.initials: JA
authors.lastname: O'Meara
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Lemke
authors.forename: Cédrickx
authors.initials: C
authors.lastname: Godbout
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
authors.forename: Lisette
authors.initials: L
authors.lastname: Lagacé
authors.forename: Benoît
authors.initials: B
authors.lastname: Moreau
authors.forename: Diane
authors.initials: D
authors.lastname: Thibeault
authors.forename: Peter W
authors.initials: PW
authors.lastname: White
authors.forename: Montse
authors.initials: M
authors.lastname: Llinàs-Brunet
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000737:chemistry*; D002460:Cell Line; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray / Q000379:methods; D024882:Drug Resistance, Viral; D005838:Genotype; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry; D017361:Viral Nonstructural Proteins / Q000737:chemistry*; D014965:X-Rays; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011480:Protease Inhibitors; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus