Orally efficacious broad-spectrum allosteric inhibitor of paramyxovirus polymerase

Robert M. Cox, Julien Sourimant, Mart Toots, Jeong Joong Yoon, Satoshi Ikegame, Mugunthan Govindarajan, Ruth E. Watkinson, Patricia Thibault, Negar Makhsous, Michelle J. Lin, Jose R. Marengo, Zachary Sticher, Alexander A. Kolykhalov, Michael G. Natchus, Alexander L. Greninger, Benhur Lee, Richard K. Plemper

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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.

Original languageEnglish
Pages (from-to)1232-1246
Number of pages15
JournalNature Microbiology
Issue number10
StatePublished - 1 Oct 2020


Dive into the research topics of 'Orally efficacious broad-spectrum allosteric inhibitor of paramyxovirus polymerase'. Together they form a unique fingerprint.

Cite this