Advances in the development of macrocyclic inhibitors of hepatitis C virus NS3-4A protease.
Hepatitis C virus (HCV) is a major cause of acute hepatitis and chronic liver disease, including cirrhosis and hepatocellular carcinoma (HCC). No vaccine is currently available to prevent hepatitis C, and the current standard of care (SOC) - pegylated interferon-α (PEG-IFN-α) in combination with ribavirin (RBV) - is only partially effective and it also presents side effects. Novel treatment options now under intensive development are focused on the discovery of inhibitors of HCV-specific enzymes. The HCV NS3 protease plays an essential role for viral replication and it is recognized as one of the most attractive targets for developing novel anti-HCV therapies. After two decades of research efforts a number of potent active-site inhibitors of the NS3 protease have been generated and some of them are in late stage of clinical trials. A particularly interesting class of HCV NS3 protease inhibitors are based on depeptidized macrocyclic structures. The article reviews the recent progresses made in the discovery and development of macrocyclic inhibitors of the HCV NS3 protease as described in the most recent scientific literature (patent excluded), from a medicinal chemistry perspective.
Istituto di Ricerche di Biologia Molecolare "P. Angeletti", Pomezia, Rome, Italy. salvatore_avolio@merck.com
Salvatore
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Avolio
Vincenzo
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Summa
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry*; D020134:Catalytic Domain; D002986:Clinical Trials as Topic; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000737:chemistry / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry*; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D047028:Macrocyclic Compounds; D011092:Polyethylene Glycols; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C100416:peginterferon alfa-2a