Current Perspective of HCV NS5B Inhibitors: A Review

Abstract

Hepatitis C virus (HCV) infection has emerged as one of the most significant disease to affect humans. Despite its large medical and economical impact, there are no vaccines or efficient therapies without major side effects. The HCV non-structural protein 5B (NS5B) is the RNA-dependent RNA polymerase responsible for the complete copy of the RNA viral genome and is a target of choice for the development of anti-HCV drugs. Although many small molecules have been identified as allosteric inhibitors of NS5B, very few are active in clinical applications. Developments in the field have prompted us to review the research work on HCV NS5B polymerase inhibitors, especially their structure activity relationships and molecular modeling studies. This review will focus on the journey of drug discovery of HCV NS5B inhibitors covering both nucleoside and non-nucleosides.

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

“…HCV NS5B Non-Nucleoside Inhibitor 42: The HCV non-structural protein 5B (NS5B), a 66 kDa RNA-dependent RNA polymerase (RdRp), serves an attractive anti-HCV target because of its key role in the replication of HCV RNA genome and humans lacks its functional equivalent 64. It is a cyclopropyl-fused indolobenzazepine class of HCV NS5B polymerase inhibitor targeted to the allosteric thumb domain I.…”

Molecular Docking and Pharmacophore-Based Virtual Screening of Novel Inhibitors for HCV NS5B RNA-Dependent RNA Polymerase Enzyme from Crude Sesame Essential Oil.

“…Moreover, in recent times, hepatitis C virus (HCV) liver infection has become a major health concerns with significant economic and medical impacts, affecting humans with about 170 million chronic sufferers estimated worldwide [5,6]. Also, it is considered as one of the primary causes of cirrhosis and hepatocellular carcinoma (HCC); and a leading cause for liver transplantation worldwide [5][6][7].…”

“…Also, it is considered as one of the primary causes of cirrhosis and hepatocellular carcinoma (HCC); and a leading cause for liver transplantation worldwide [5][6][7]. In addition, HCV belongs to the familyFlaviviridae and genus-hepacivirus [8].…”

“…[11]. In addition, studies have shown that there have been no effective vaccines or therapy without any significant side effects [6,9,11].…”

“…Furthermore, a growing number of small molecules have been reported as allosteric inhibitors of NS5B with only a very few of them still active in clinical trials in recent times [5][6][7]. However, limited studies are available on medicinal small molecules, as HCV NS5B RNA-dependent, RNA polymerase inhibitors from other plants like Acacia concinna [9], Phyllanthus niruri [10].…”