MK-0608

1.Viral RNA Polymerase Inhibitors/Todd Appleby i-hung shi and Wei understand zhong/02 May 2009
abstract:Infections by RNA viruses continue to exist as significant public health problems worldwide. In response to the urgent need for safer and more efficacious treatment options against infections caused by RNA viruses, the pharmaceutical and biotechnology industries have devoted significant efforts over the last two decades to discovering and developing new antiviral agents. As the primary viral enzyme responsible for genome replication and transcription, RNA-dependent RNA polymerases (RdRps) emerged early and remained as one of the most promising targets for therapeutic intervention of RNA virus infections. Advances in both basic research and drug discovery technology have resulted in the identification of a significant number of nucleoside (NIs) and non-nucleoside inhibitors (NNIs) of viral RdRps. In this chapter, we will focus our attention on various classes of viral RdRp inhibitors, with main emphases on those of hepatitis C virus (HCV) due to its significant unmet medical need. Recent progress in understanding their mechanism of action, antiviral activity profiles, and emergence of drug resistance mutations will be discussed.
2.Approaches for the Development of Antiviral Compounds: The Case of Hepatitis C Virus/Raymond F. SchinaziEmail authorSteven J. CoatsLeda C. BassitJohan LennerstrandJames H. NettlesSelwyn J. Hurwitz
abstract:Traditional methods for general drug discovery typically include evaluating random compound libraries for activity in relevant cell-free or cell-based assays. Success in antiviral development has emerged from the discovery of more focused libraries that provide clues about structure activity relationships. Combining these with more recent approaches including structural biology and computational modeling can work efficiently to hasten discovery of active molecules, but that is not enough. There are issues related to biology, toxicology, pharmacology, and metabolism that have to be addressed before a hit compound becomes nominated for clinical development. The objective of gaining early preclinical knowledge is to reduce the risk of failure in Phases 1, 2, and 3, leading to the goal of approved drugs that benefit the infected individual. This review uses hepatitis C virus (HCV), for which we still do not have an ideal therapeutic modality, as an example of the multidisciplinary efforts needed to discover new antiviral drugs for the benefit of humanity.