Orally efficacious broad-spectrum allosteric inhibitor of paramyxovirus polymerase

  • Nat Microbiol. 2020 Oct;5(10):1232-1246. doi: 10.1038/s41564-020-0752-7.
Robert M Cox  1 ,  Julien Sourimant  1 ,  Mart Toots  1 ,  Jeong-Joong Yoon  1 ,  Satoshi Ikegame  2 ,  Mugunthan Govindarajan  3 ,  Ruth E Watkinson  2 ,  Patricia Thibault  2 ,  Negar Makhsous  4 ,  Michelle J Lin  4 ,  Jose R Marengo  3 ,  Zachary Sticher  3 ,  Alexander A Kolykhalov  3 ,  Michael G Natchus  3 ,  Alexander L Greninger  4 ,  Benhur Lee  2 ,  Richard K Plemper  5
Affiliations
  • 1. Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
  • 2. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 3. Emory Institute for Drug Development, Emory University, Atlanta, GA, USA.
  • 4. Virology Division, Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
  • 5. Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. [email protected].
PMID: 32661315 DOI: 10.1038/s41564-020-0752-7
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.

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