Discovery of an Oral Respiratory Syncytial Virus (RSV) Fusion Inhibitor (GS-5806) and Clinical Proof of Concept in a Human RSV Challenge Study

Abstract

GS-5806 is a novel, orally bioavailable RSV fusion inhibitor discovered following a lead optimization campaign on a screening hit. The oral absorption properties were optimized by converting to the pyrazolo[1,5-a]-pyrimidine heterocycle, while potency, metabolic, and physicochemical properties were optimized by introducing the para-chloro and aminopyrrolidine groups. A mean EC50 = 0.43 nM was found toward a panel of 75 RSV A and B clinical isolates and dose-dependent antiviral efficacy in the cotton rat model of RSV infection. Oral bioavailability in preclinical species ranged from 46 to 100%, with evidence of efficient penetration into lung tissue. In healthy human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a mean 4.2 log10 reduction in peak viral load and a significant reduction in disease severity compared to placebo. In conclusion, a potent, once daily, oral RSV fusion inhibitor with the potential to treat RSV infection in infants and adults is reported.

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

“…To identify novel RSV inhibitors, an antiviral high-throughputscreening campaign was conducted on a small-molecule library, and hits were selected for extensive chemical optimization. The most potent and selective hit active against both RSV A and B was extensively optimized for potency, prolonged metabolic stability, oral delivery, and respiratory tissue distribution (17). These efforts yielded GS-5806, a potent inhibitor of RSV replication with a mean EC 50 of 0.37 nM in primary HAE cells, which are believed to be the main target for RSV replication in vivo.…”

“…1) (17). Once-daily oral administration of GS-5806 to healthy adult volunteers experimentally infected with RSV strain M37 was safe and well tolerated and resulted in a significant reduction of both the viral titer and disease severity (24).…”

“…These inhibitors partition into three categories based upon their different mechanisms of action: (i) nucleocapsid protein inhibitors (RSV604) (10), (ii) RNA-dependent RNA polymerase inhibitors (YM-53403, BI-D, and ALS-8176) (11)(12)(13), and (iii) fusion inhibitors (VP-14637, TMC-353121, BMS-433771, and GS-5806) (14)(15)(16)(17). Among these, RSV fusion inhibitors are the most potent class in vitro and exhibit efficacy in animal models of RSV infection (14)(15)(16)(17). Currently, only ALS-8176 and GS-5806 are being clinically developed for the treatment of RSV infection.…”

Respiratory Syncytial Virus Attachment Glycoprotein Contribution to Infection Depends on the Specific Fusion Protein

“…Thus far, there are no licensed vaccines, although there are multiple vaccine candidates undergoing clinical trials (3). Development of antivirals against RSV is also an active field of research and clinical development (4)(5)(6).…”

Antiviral Efficacy of a Respiratory Syncytial Virus (RSV) Fusion Inhibitor in a Bovine Model of RSV Infection

“…viral therapeutics was validated using GS1, a novel small-molecule inhibitor with potent in vitro activity against both bRSV and hRSV. GS1 is a close structural analog of GS-5806, which is currently in clinical development for treatment of RSV infection (43).…”