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GS-5806 Inhibits a Broad Range of Respiratory Syncytial Virus Clinical Isolates by Blocking the Virus-Cell Fusion Process

Lookup NU author(s): Emeritus Professor Geoffrey Toms

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Abstract

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in infants and young children. In addition, RSV causes significant morbidity and mortality in hospitalized elderly and immunocompromised patients. Currently, only palivizumab, a monoclonal antibody against the RSV fusion (F) protein, and inhaled ribavirin are approved for the prophylactic and therapeutic treatment of RSV, respectively. Therefore, there is a clinical need for safe and effective therapeutic agents for RSV infections. GS-5806, discovered via chemical optimization of a hit from a high-throughput antiviral-screening campaign, selectively inhibits a diverse set of 75 RSV subtype A and B clinical isolates (mean 50% effective concentration [EC50] = 0.43 nM). The compound maintained potency in primary human airway epithelial cells and exhibited low cytotoxicity in human cell lines and primary cell cultures (selectivity > 23,000-fold). Time-of-addition and temperature shift studies demonstrated that GS-5806 does not block RSV attachment to cells but interferes with virus entry. Follow-up experiments showed potent inhibition of RSV F-mediated cell-to-cell fusion. RSV A and B variants resistant to GS-5806, due to mutations in F protein (RSV A, L138F or F140L/N517I, and RSV B, F488L or F488S), were isolated and showed cross-resistance to other RSV fusion inhibitors, such as VP-14637, but remained fully sensitive to palivizumab and ribavirin. In summary, GS-5806 is a potent and selective RSV fusion inhibitor with antiviral activity against a diverse set of RSV clinical isolates. The compound is currently under clinical investigation for the treatment of RSV infection in pediatric, immunocompromised, and elderly patients.

Publication metadata

Author(s): Perron M, Stray K, Kinkade A, Theodore D, Lee G, Eisenberg E, Sangi M, Gilbert BE, Jordan R, Piedra PA, Toms GL, Mackman R, Cihlar T

Publication type: Article

Publication status: Published

Journal: Antimicrobial Agents and Chemotherapy

Year: 2016

Volume: 60

Issue: 3

Pages: 1264-1273

Print publication date: 01/03/2016

Online publication date: 14/12/2015

Acceptance date: 05/11/2015

ISSN (print): 0066-4804

ISSN (electronic): 1098-6596

Publisher: American Society for Microbiology

URL: http://dx.doi.org/10.1128/AAC.01497-15

DOI: 10.1128/AAC.01497-15

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