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.
Highlights
Hepatitis means inflammation of the liver and Hepatitis C virus (HCV) is one of the major causes
Later in 2011 first generation direct acting anti-virals [DAA]-NS3/4A protease inhibitors namely Telaprevir [Incivek], Boceprevir [Victrelis] were launched, but their use is restricted to patients infected with HCV genotype 1 [6, 7]
Over a decade efforts were focused towards development of specific inhibitors of the viral RNA-dependent RNA polymerase NS5B as it is the key enzyme for viral replication, conserved among the HCV genotypes 1, 2, 3, 4, 5 and 6, has an active site and many allosteric binding pockets [8]
Summary
Hepatitis means inflammation (a painful reddish swelling) of the liver and Hepatitis C virus (HCV) is one of the major causes. Patients can relapse and develop infection due to the presence of variants of the virus [quasispecies] arising from error-prone replication [3]. Later in 2011 first generation direct acting anti-virals [DAA]-NS3/4A protease inhibitors namely Telaprevir [Incivek], Boceprevir [Victrelis] were launched, but their use is restricted to patients infected with HCV genotype 1 [6, 7]. Over a decade efforts were focused towards development of specific inhibitors of the viral RNA-dependent RNA polymerase NS5B as it is the key enzyme for viral replication, conserved among the HCV genotypes 1, 2, 3, 4, 5 and 6, has an active site and many allosteric binding pockets [8]. A major breakthrough in Hepatitis C research came with the launch of Sofosbuvir [Sovaldi] in December 2013, an NS5B inhibitor developed by Gilead. Hepatitis C therapies launched from 2014 to till date were furnished in Table 1 [10]
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