ePrints@IIScePrints@IISc Home | About | Browse | Latest Additions | Advanced Search | Contact | Help

Potent HCV NS3 Protease Inhibition by a Water-Soluble Phyllanthin Congener

Uma Reddy, B and Tandon, H and Pradhan, MK and Adhikesavan, H and Srinivasan, N and Das, S and Jayaraman, N (2020) Potent HCV NS3 Protease Inhibition by a Water-Soluble Phyllanthin Congener. In: ACS Omega, 5 (20). pp. 11553-11562.

acs_ome_5-20_11553-11562_2020.pdf - Published Version

Download (2MB) | Preview
ao0c00786_si_001.pdf - Published Supplemental Material

Download (400kB) | Preview
Official URL: http://dx.doi.org/10.1021/acsomega.0c00786


NS3/4A protease of hepatitis C virus (HCV) plays an important role in viral RNA replication. A 1,4-diphenylbutanedicarboxylic acid derivative, namely, phyllanthin, extracted from the leaf of a herbal plant, Phyllanthus amarus, inhibits HCV NS3/4A protease and replication activities. However, the reduced aqueous solubility, high toxicity, and poor oral bioavailability are major impediments with phyllanthin. We herein present a design approach to generate phyllanthin congeners in order to potentiate inhibition activity against protease. The phyllanthin congeners were synthesized by chemical methods and subjected to systematic biological studies. One of the congeners, annotated as D8, is identified as a novel and potent inhibitor of the HCV-NS3/4Aprotease activity in vitro and the viral RNA replication in cell culture. Structural analysis using the computational-based docking approach demonstrated important noncovalent interactions between D8 and the catalytic residues of the viral protease. Furthermore, D8 was found to be significantly nontoxic in cell culture. More importantly, oral administration of D8 in BALB/c mice proved its better tolerability and bioavailability, as compared to native phyllanthin. Taken together, this study reveals a promising candidate for developing anti-HCV therapeutics to control HCV-induced liver diseases. Copyright © 2020 American Chemical Society.

Item Type: Journal Article
Publication: ACS Omega
Publisher: American Chemical Society
Additional Information: The copyright for this article belongs to the American Chemical Society
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Division of Biological Sciences > Microbiology & Cell Biology
Division of Chemical Sciences > Organic Chemistry
Date Deposited: 05 Nov 2021 09:25
Last Modified: 05 Nov 2021 09:25
URI: http://eprints.iisc.ac.in/id/eprint/65872

Actions (login required)

View Item View Item