Viral protease inhibitors.
This review provides an overview of the development of viral protease inhibitors as antiviral drugs. We concentrate on HIV-1 protease inhibitors, as these have made the most significant advances in the recent past. Thus, we discuss the biochemistry of HIV-1 protease, inhibitor development, clinical use of inhibitors, and evolution of resistance. Since many different viruses encode essential proteases, it is possible to envision the development of a potent protease inhibitor for other viruses if the processing site sequence and the catalytic mechanism are known. At this time, interest in developing inhibitors is limited to viruses that cause chronic disease, viruses that have the potential to cause large-scale epidemics, or viruses that are sufficiently ubiquitous that treating an acute infection would be beneficial even if the infection was ultimately self-limiting. Protease inhibitor development is most advanced for hepatitis C virus (HCV), and we also provide a review of HCV NS3/4A serine protease inhibitor development, including combination therapy and resistance. Finally, we discuss other viral proteases as potential drug targets, including those from Dengue virus, cytomegalovirus, rhinovirus, and coronavirus.
Anderson
Jeffrey
J
Division of Infectious Diseases, Department of Internal Medicine, University of Massachusetts, Worcester, MA, USA.
Schiffer
Celia
C
Lee
Sook-Kyung
SK
Swanstrom
Ronald
R
D000086042:3C Viral Proteases; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D003546:Cysteine Endopeptidases; D003587:Cytomegalovirus / Q000187:drug effects / Q000201:enzymology; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D010447:Peptide Hydrolases / Q000737:chemistry*; D011480:Protease Inhibitors / Q000494:pharmacology*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects / Q000201:enzymology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D014764:Viral Proteins / Q000037:antagonists & inhibitors; D014780:Viruses / Q000187:drug effects* / Q000201:enzymology*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000086042:3C Viral Proteases; D000998:Antiviral Agents; D003546:Cysteine Endopeptidases; D017320:HIV Protease Inhibitors; D010447:Peptide Hydrolases; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases