Advances in the development of new therapeutic agents targeting the NS3-4A serine protease or the NS5B RNA-dependent RNA polymerase of the hepatitis C virus.
The HCV NS3 protease and NS5B polymerase play essential roles in the replication of the hepatitis C virus (HCV). Following the successful paradigm established for HIV protease and reverse transcriptase inhibitors, these enzymes have been elected as targets for the development of small molecule HCV inhibitors. By combining the power of high-throughput screening with rational, knowledge-based drug discovery, a number of competitive inhibitors of the NS3 protease as well as nucleoside and non-nucleoside inhibitors of the NS5B polymerase have been identified and some have now entered clinical trials. In this article we review recent progress in the discovery and development of small molecule inhibitors of these two essential viral enzymes as they are advancing in the clinic.
De Francesco
Raffaele
R
Istituto di Ricerche di Biologia Molecolare, P. Angeletti, Via Pontina Km 30,600, 00040 Pomezia (Rome), Italy. raffaele_defrancesco@merck.com
Carfí
Andrea
A
D000818:Animals; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016174:Hepacivirus / Q000187:drug effects / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D015394:Molecular Structure; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase