5 Inhibitors of Hepatitis C Virus NS3•4A Protease: An Overdue Line of Therapy

Abstract

Publisher Summary The chapter reviews that one cannot separate the medicinal chemistry research into HCV NS3.4A protease inhibitors from the virological research devoted to the development of assays and models. The lack of cellular and animal model systems has hampered progress in the field. This is beginning to change. The construction of an HCV replicon, for example, should lead to assay systems that include most of the HCV genome in cell culture. The development of animal models is progressing more slowly. While the chimpanzee model is generally accepted as the most reliable, it is still not validated. The cost associated with such primate models, as well as ethical considerations preclude its use for screening large numbers of molecules. While clear progress in inhibitor design is being made, much work remains to be done. Inhibitory potencies against the NS3.4A proteases are improving rapidly particularly with peptide-based inhibitors, but the most potent compounds are still not drug-like: They are large, charged, and unlikely to penetrate cells. It discusses that non-peptic inhibitors are even further from the finishing line. Library screening has yielded a number of classes of inhibitory compounds, but the potencies are less than those of peptidomimetic compounds. The chapter also reviews that recent advances in cellular replication systems, X-ray, NMR and SAR analyses are allowing researchers to begin to crack HCV's secrets. The understanding of the subtleties of the enzyme function and structure will, in the not too distant future, yield useful, marketable protease inhibitors, which will revolutionize the treatment of hepatitis C in the same manner that HIV protease inhibitors revolutionized therapy for AIDS patients.