Approaches for the development of antiviral compounds: the case of hepatitis C virus.
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.
Schinazi
Raymond F
RF
Laboratory of Biochemical Pharmacology, VA Medical Center, Emory University School of Medicine, 1670 Clairmont Road, Decatur, GA 30033, USA. rschina@emory.edu
Coats
Steven J
SJ
Bassit
Leda C
LC
Lennerstrand
Johan
J
Nettles
James H
JH
Hurwitz
Selwyn J
SJ
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy* / Q000201:enzymology / Q000821:virology*; D006801:Humans; D021281:Quantitative Structure-Activity Relationship
D000998:Antiviral Agents; D004791:Enzyme Inhibitors