Cyclopeptide Kalata B12 as HCV-NS5A potent Inhibitor

Abstract

Hepatitis C Virus (HCV) is the leading cause of liver diseases globally, causing severe complications such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Despite the advent of successful regimens, still, 71 million individuals are chronically infected every year. Therefore, more accessible novel therapies are needed to fight the challenges such as adverse effects, genotype selectivity, and resistance to these regimens due to viral mutations. HCV NS5A is a non-structural phosphoprotein, with its pivotal role in viral replication assembly, and has been the target of continuous research. Cyclopeptides are an emerging class of peptides reported to have antiviral, anticancer, and antimicrobial properties. These cyclopeptides have exceptional resistance to thermal, chemical, or enzymatic degradation. Herein, we present the inhibitory potential of cyclopeptide Kalata B12 against the HCV NS5A gene. Objective: To investigate the antiviral potential of Kalata B2, Kalata B12, and cycloviolacin O14 against HCV NS5A Methods: We investigated thirty cyclopeptides through molecular docking analysis for their anti-HCV-NS5A inhibition potential. Three cyclopeptides, Kalata B2, Kalata B12, and cycloviolacin O14 showed minimum binding energies, for their antiviral potential. The defense-related, circular mini-protein Kalata B12 showed an impressive docking score of -9.80 Kcal/mol. Further, it was synthesized and went through cytotoxicity analysis via MTT assay on HepG2 cell line, which showed more than 85% cell viability at submicromolar concentrations. Results: The peptide Kalata B12 showed significant (***P<0.0001) inhibition of NS5A gene (approx. 75%) at 100nM in In vitro trials, confirmed by real-Time PCR analysis. Conclusions: Kalata B12 cyclopeptide was found to be a potential HCV NS5A inhibitor