Orally efficacious lead of the AVG inhibitor series targeting a dynamic interface in the respiratory syncytial virus polymerase

• Type of Material: Article
• Authors: Julien Sourimant, Georgia State University; Carolin M Lieber, Georgia State University; Jeong-Joong Yoon, Georgia State University; Mart Toots, Georgia State University; Mugunthan Govindarajan, Emory University; Venkata Udumula, Emory University; Kaori Sakamoto, University of Georgia; Michael Natchus, Emory University; Joseph Patti, Aviragen Therapeutics Inc; John Vernachio, Aviragen Therapeutics Inc; Richard Plemper, Emory University
• Language: English
• Date: 2022-06-24
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Scienc
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.abo2236
• Title of Journal or Parent Work: SCIENCE ADVANCES
• Volume: 8
• Issue: 25
• Start Page: eabo2236
• End Page: eabo2236
• Grant/Funding Information: This work was supported, in part, by NIH grants AI071002 (R.K.P.), AI153400 (R.K.P.), and HD079327 (R.K.P.). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
• Keywords: TRANSCRIPTION; PHOSPHOPROTEIN; Multidisciplinary Sciences; YOUNG-CHILDREN; REPLICATION; L PROTEIN; Science & Technology - Other Topics; REDUCES HOSPITALIZATION; Science & Technology; COMPLEX; PALIVIZUMAB; VESICULAR STOMATITIS-VIRUS; IDENTIFICATION

Abstract

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory infections in infants and the immunocompromised, yet no efficient therapeutic exists. We have identified the AVG class of allosteric inhibitors of RSV RNA synthesis. Here, we demonstrate through biolayer interferometry and in vitro RNA-dependent RNA polymerase (RdRP) assays that AVG compounds bind to the viral polymerase, stalling the polymerase in initiation conformation. Resistance profiling revealed a unique escape pattern, suggesting a discrete docking pose. Affinity mapping using photoreactive AVG analogs identified the interface of polymerase core, capping, and connector domains as a molecular target site. A first-generation lead showed nanomolar potency against RSV in human airway epithelium organoids but lacked in vivo efficacy. Docking pose-informed synthetic optimization generated orally efficacious AVG-388, which showed potent efficacy in the RSV mouse model when administered therapeutically. This study maps a druggable target in the RSV RdRP and establishes clinical potential of the AVG chemotype against RSV disease.