A Review on Anti-HCV Agents Targeting Active Site and Allosteric Sites of Non-Structural Protein 5b [Ns5b]

Abstract

Hepatitis C, a chronic disease affecting the global population significantly is caused majorly by Hepatitis C virus [HCV]. Among the several druggable targets explored for Hepatitis C, the viral protein, non-structural protein 5B [NS5B] is the target of choice for researchers as it is the key enzyme in the HCV replication and its active site is conserved among all genotypes. In the recent years the landscape of Hepatitis C therapies, have evolved from Peg-Interferon [PEG-INF]/Ribavirin, to directly acting anti-virus along with PEG-INF and finally, INF free regimens with greater than 90% sustained virological response [SVR]. The launch of Sofosbuvir, a nucleotide inhibitor of NS5B marks the major paradigm in hepatitis C research. Sofosbuvir exhibits, pan-genotypic activity, low barrier to resistance, highly effective and safe. However, the high prices of these medications limit their universal access. This review will focus on progress towards the discovery and development of NS5B inhibitors targeting allosteric sites and active site, covering the chemical class and structure-activity relationships.

Review on chemogenomic approaches towards hepatitis C viral targets

“…Allosteric site C present in the palm region and it is targeted by proline sulfonamides, acylpyrrolidines, acrylic acid derivatives, and benzothiadiazines. 81 Site D is targeted by benzofurans and some inhibitors target allosteric site E through different mechanism. 82 Sofosbuvir is a nucleotide analog that controls the effect of S282T mutation in NS5B protein.…”

“…Indoles and benzimidazoles inhibitors target the allosteric site A located in the thumb domain, similarly, the pyranindoles, thiophenes, dihydroxyrhones, and phenylalanine derivatives target the site B located in thumb domain of RdRp. Allosteric site C present in the palm region and it is targeted by proline sulfonamides, acyl‐pyrrolidines, acrylic acid derivatives, and benzothiadiazines . Site D is targeted by benzofurans and some inhibitors target allosteric site E through different mechanism .…”

Sofosbuvir: Treatment of Chronic Hepatitis C and the Main Trends in Patent Protection

“…There is no doubt that effective antiviral therapy leading to the eradication of HCV infection reduces the risk of progression of hepatic and extrahepatic HCV infection manifestations, especially if the treatment is carried out before the formation of liver cirrhosis [9][10][11][12][13][14][15][16][17].…”

Antihepatitis C Virus Activity of Indonesian Mahogany (Toona Sureni)

“…Many therapies for HCV infection have been developed, but the therapeutic efficacy still needs to be improved [6]. In future, anti-HCV research should aim at the development of therapies for non-responder patient population and treatment regiments with short duration of treatment [7].…”