Synergy of small molecular inhibitors of hepatitis C virus replication directed at multiple viral targets.
Chronic hepatitis C virus (HCV) infection is a significant worldwide health problem with limited therapeutic options. A number of novel, small molecular inhibitors of HCV replication are now entering early clinical trials in humans. Resistance to small molecular inhibitors is likely to be a significant hurdle to their use in patients. A systematic assessment of combinations of interferon and/or novel anti-hepatitis C virus agents from several different mechanistic classes was performed in vitro. Combinations of inhibitors with different mechanisms of action consistently demonstrated more synergy than did compounds with similar mechanisms of action. These results suggest that combinations of inhibitors with different mechanisms of action should be prioritized for assessment in clinical trials for chronic hepatitis C virus infection.
Wyles
David L
DL
Department of Medicine, Divivion of Infectious Diseases, University of California-San Diego, 9500 Gilman Drive, MC 0711, La Jolla, CA 92093, USA. dwyles@ucsd.edu
Kaihara
Kelly A
KA
Vaida
Florin
F
Schooley
Robert T
RT
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D017930:Genes, Reporter; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins; D012093:Replicon / Q000187:drug effects; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D011480:Protease Inhibitors; D011993:Recombinant Fusion Proteins; D008156:Luciferases