Orally efficacious broad-spectrum allosteric inhibitor of paramyxovirus polymerase

• Type of Material: Article
• Authors: Robert M. Cox, Georgia State University; Julien Sourimant, Georgia State University; Mart Toots, Georgia State University; Jeong-Joong Yoon, Georgia State University; Satoshi Ikegame, Icahn School of Medicine at Mount Sinai; Mugunthan Govindarajan, Emory University; Ruth E. Watkinson, Icahn School of Medicine at Mount Sinai; Patricia Thibault, Icahn School of Medicine at Mount Sinai; Negar Makhsous, University of Washington; Michelle J. Lin, University of Washington; Jose R. Marengo, Emory University; Zachary Sticher, Emory University; Alexander Kolykhalov, Emory University; Michael Natchus, Emory University; Alexander L. Greninger, University of Washington; Benhur Lee, Icahn School of Medicine at Mount Sinai; Richard Plemper, Emory University
• Language: English
• Date: 2020-07-13
• Publisher: NATURE PORTFOLIO
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41564-020-0752-7
• Title of Journal or Parent Work: NATURE MICROBIOLOGY
• Volume: 5
• Issue: 10
• Start Page: 1232
• End Page: +
• Grant/Funding Information: This work was supported, in part, by Public Health Service grants AI071002 (to RKP) and HD079327 (to RKP), from the NIH/NIAID and NIH/NICHD, respectively. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
• Keywords: DRUGS; HEPATITIS-C; PARAINFLUENZA VIRUS; IDENTIFICATION; RESPIRATORY SYNCYTIAL VIRUS; Science & Technology; ANTIVIRAL THERAPY; MEASLES-VIRUS; Microbiology; PROTEIN; INFECTION; Life Sciences & Biomedicine; PATHOGENESIS
• Research Categories: Biology, Virology; Health Sciences, Pathology; Biology, Microbiology

Abstract

Paramyxoviruses such as human parainfluenza virus type-3 (HPIV3) and measles virus (MeV) are a substantial health threat. In a high-throughput screen for inhibitors of HPIV3 (a major cause of acute respiratory infection), we identified GHP-88309—a non-nucleoside inhibitor of viral polymerase activity that possesses unusual broad-spectrum activity against diverse paramyxoviruses including respiroviruses (that is, HPIV1 and HPIV3) and morbilliviruses (that is, MeV). Resistance profiles of distinct target viruses overlapped spatially, revealing a conserved binding site in the central cavity of the viral polymerase (L) protein that was validated by photoaffinity labelling-based target mapping. Mechanistic characterization through viral RNA profiling and in vitro MeV polymerase assays identified a block in the initiation phase of the viral polymerase. GHP-88309 showed nanomolar potency against HPIV3 isolates in well-differentiated human airway organoid cultures, was well tolerated (selectivity index > 7,111) and orally bioavailable, and provided complete protection against lethal infection in a Sendai virus mouse surrogate model of human HPIV3 disease when administered therapeutically 48 h after infection. Recoverees had acquired robust immunoprotection against reinfection, and viral resistance coincided with severe attenuation. This study provides proof of the feasibility of a well-behaved broad-spectrum allosteric antiviral and describes a chemotype with high therapeutic potential that addresses major obstacles of anti-paramyxovirus drug development.