Asymmetric Binding to NS5A by Daclatasvir (BMS-790052) and Analogs Suggests Two Novel Modes of HCV Inhibition

• Type of Material: Article
• Authors: James Nettles, Emory University; Richard A. Stanton, Emory University; Joshua Broyde, Emory University; Franck Amblard, Emory University; HongWang Zhang, Emory University; Longhu Zhou, Emory University; Junxing Shi, RFS Pharma, LLC; Tamara R. McBrayer, Veterans Affairs Medical Center; Tony Whitaker, RFS Pharma, LLC; Steven J. Coats, RFS Pharma, LLC; James Kohler, Emory University; Raymond Schinazi, Emory University
• Language: English
• Date: 2014-12-11
• Publisher: American Chemical Society
• Publication Version: Final Published Version
• Copyright Statement: © 2014 American Chemical Society.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1021/jm501291c
• Title of Journal or Parent Work: Journal of Medicinal Chemistry
• ISSN: 0022-2623
• Volume: 57
• Issue: 23
• Start Page: 10031
• End Page: 10043
• Grant/Funding Information: Supported by Grant NIGMS P41-GM103311.; This work was supported in part by NIH CFAR Grants 2P30-AI-050409 and the Department of Veterans Affairs.
• Keywords: Chemistry, Medicinal; REPLICATION COMPLEX INHIBITOR; Life Sciences & Biomedicine; VARIANTS; Pharmacology & Pharmacy; HEPATITIS-C VIRUS; RESISTANT; CRYSTAL-STRUCTURE; Science & Technology; DOMAIN; DISCOVERY; PROTEIN; SORTING NEXIN 5; POTENT
• Research Categories: Chemistry, Pharmaceutical; Health Sciences, Pharmacology

Abstract

Symmetric, dimeric daclatasvir (BMS-790052) is the clinical lead for a class of picomolar inhibitors of HCV replication. While specific, resistance-bearing mutations at positions 31 and 93 of domain I strongly suggest the viral NS5A as target, structural mechanism(s) for the drugs activities and resistance remains unclear. Several previous models suggested symmetric binding modes relative to the homodimeric target; however, none can fully explain SAR details for this class. We present semiautomated workflows to model potential receptor conformations for docking. Surprisingly, ranking docked hits with our library-derived 3D-pharmacophore revealed two distinct asymmetric binding modes, at a conserved poly-proline region between 31 and 93, consistent with SAR. Interfering with protein-protein interactions at this membrane interface can explain potent inhibition of replication-complex formation, resistance, effects on lipid droplet distribution, and virion release. These detailed interaction models and proposed mechanisms of action will allow structure-based design of new NS5A directed compounds with higher barriers to HCV resistance.