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Abstract

Globally, Hepatitis C virus (HCV) is a leading cause of chronic liver disease, hepatocellular carcinoma and cirrhosis and the most common reason for liver transplantation. Presently, the most common treatment for HCV infected patients is the combinations of pegylated interferon and ribavirin that provide a sustained response in patients, but its side effects are brutal. Therefore, attempts have been made to target the two important enzymes, NS3 protease and NS5B RNA polymerase, that are crucial for the replication of HCV. The article presents the development of some NS3/4A protease inhibitors that have reached the final stages of clinical trials. Keywords: IntroductionHepatitis C virus (HCV) belongs to the family of Flaviviridae. This family also includes other viruses responsible for severe human diseases, such as yellow fever virus, dengue virus, St. Louis encephalitis virus, and West Nile virus. About 170 million people, estimating 3% of the global population are infected with HCV. Chronic HCV infection may lead to progressive liver injury, cirrhosis and in some cases hepatocellular carcinoma [1]. Hepatitis C virus is an envelope, positive single stranded RNA. Its genome is composed of 9.5kb and encodes a 3000 amino acid sequence residue polyprotein [2]. For HCV entry, human CD81 receptor is required which binds directly with E2 protein of HCV. This CD81 receptor is a widely distributed cell-surface tetraspanin that participates in the formation of molecular complexes on various cell types like hepatocytes, natural killer cells, B-lymphocytes, and T-lymphocytes. Thus, the HCV not only exploits hepatocytes but also modulates the host immune response.The HCV has principally two drug targets, its RNA polymerase and the protease enzymes. where the former catalyzes the RNA relication. This RNA-dependent RNA-polymerase (RdRp), however, lacks a proof reading activity which leads to a high mutation rate and a large number of mutations [3]. The HCV encodes a polyprotein of approximately 3000 amino acids [4], which is cleaved cotranslationally and post-translationally to produce four structural proteins (C, E1, E2, and p7) and six nonstructural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) [5][6][7]. Only the NS3-NS5B region of the polyprotein is required for genome replication in cell culture. NS3-NS4A, in which NS4A acts as a cofactor, is a serine protease belonging to trypsin/chemotrypsin superfamily. NS4A directs the localization of NS3 and modulates its enzyme activity [8]. NS3-NS4A is simply written as NS3/4A.It plays a critical role in producing the important components for viral replication by cleaving the scissile bond between NS3-NS4A. Based on the available structure of HCV protease, there are three possible sites for drug design, namely zinc binding site, NS4A binding groove, and substrate binding site, of which the last one has been found to be more promising. However, the design and development of NS3/4A inhibitors is more challenging than the design of inhibitors of other proteases such as...