title: GS-5806 Inhibits a Broad Range of Respiratory Syncytial Virus Clinical Isolates by Blocking the Virus-Cell Fusion Process.
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.
authors.affiliation: Gilead Sciences, Foster City, California, USA michel.perron@gilead.com.
authors.forename: Michel
authors.initials: M
authors.lastname: Perron
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Stray
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: April
authors.initials: A
authors.lastname: Kinkade
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Theodore
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Eisenberg
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Sangi
authors.affiliation: Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Gilbert
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Jordan
authors.affiliation: Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Piedra
authors.affiliation: Newcastle University, Newcastle upon Tyne, England.
authors.forename: Geoffery L
authors.initials: GL
authors.lastname: Toms
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Mackman
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001980:Bronchi / Q000166:cytology / Q000821:virology; D002459:Cell Fusion; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007191:Indazoles; D011720:Pyrazoles / Q000494:pharmacology*; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity; D013449:Sulfonamides / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007191:Indazoles; D011720:Pyrazoles; D013449:Sulfonamides; C000591241:presatovir