The Hepatitis C Virus NS3 Protein: A Model RNA Helicase and Potential Drug Target

Abstract

The C-terminal portion of hepatitis C virus (HCV) nonstructural protein 3 (NS3) forms a three domain polypeptide that possesses the ability to travel along RNA or single-stranded DNA (ssDNA) in a 3' to 5' direction. Fueled by ATP hydrolysis, this movement allows the protein to displace complementary strands of DNA or RNA and proteins bound to the nucleic acid. HCV helicase shares two domains common to other motor proteins, one of which appears to rotate upon ATP binding. Several models have been proposed to explain how this conformational change leads to protein movement and RNA unwinding, but no model presently explains all existing experimental data. Compounds recently reported to inhibit HCV helicase, which include numerous small molecules, RNA aptamers and antibodies, will be useful for elucidating the role of a helicase in positive-sense single-stranded RNA virus replication and might serve as templates for the design of novel antiviral drugs.

Genetically Encoded Detection of Biosynthetic Protease Inhibitors

“…These enzymes, which catalyze the hydrolysis of peptide bonds, coordinate the dynamic remodelingand functional rewiringof the complex protein systems that underlie blood clotting, tissue repair, and viral assembly, among other biochemical feats. − The first clinically approved protease inhibitor targeted HIV-1 protease (HIVpro), which cleaves polyproteins into functional subunits of the HIV virion; today, this enzyme is the target of 10 approved drugs . Over the years, proteases have emerged as important targets for other viral diseasesnotably, hepatitis C and coronavirus infectious disease-19 (COVID-19)as well as cardiovascular disorders and cancer . Despite their therapeutic promise, proteases often evolve resistance mutations, which can emerge early in clinical trials, and remain subject to the same slow development timelines that plague other drugs .…”