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. H uman respiratory syncytial virus (RSV) is the predominant cause of bronchiolitis and pneumonia in infants and young children (1). Those most at risk for severe RSV disease are infants born prematurely (Ͻ34 weeks gestation) or less than 6 weeks of age and children with underlying medical conditions, such as bronchopulmonary dysplasia, congenital heart disease, or immunodeficiency (1-3). Severe RSV infection in children less than 1 year old is associated with recurrent wheezing and asthma later in life (4). RSV is also an important cause of lower respiratory tract infections in immunocompromised individuals and the elderly, often resulting in significant morbidity and mortality (5-7).Currently, there is no effective vaccine available for the prevention of RSV infection. Current approved therapeutic options for RSV include palivizumab (Synagis), a neutralizing monoclonal antibody against the RSV F protein, and inhaled ribavirin (Virazole), a broad-spectrum nucleoside analog targeting RNA transcription/replication. Palivizumab is approved for the prophylactic treatment of pediatric patients at high risk of developing severe RSV infection, whereas ribavirin is the only antiviral approved for RSV treatment (8). However, contradictory observations regarding the efficacy, concerns about tolerability, and challenging routes of administration have significantly limited the use of inhaled ribavirin (9). Therefore, there is a clinical need for a safe and effective therapeutic for pediatric and adult RSV infections. Recently, a number of small-molecule RSV inhibitors have been identified. 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) (11-13), and (iii) fusion inhibitors (VP-14637, TMC-353121, BMS-433771, and GS-5806) (14-17). Among these, RSV fusion inhibitors are the most potent class in vitro and exhibit efficacy in animal models of RSV infection (14-17). Currently, only ALS-8176 and GS-5806 are being clinically developed for the treatment of RSV infection.RSV is an enveloped virus with a negative-sense, single-stranded RNA genome. RSV infection is initiated by attachment of the viral glycoprotein (G) to the cell surface. Following attachment, the RSV fusion protein (F) mediates fusion of the viral and cellular membranes, allowing the viral replication complex to enter the cell. Spread of RSV infection occurs either through cel...

The antiviral effects of RSV fusion inhibitor, MDT‐637, on clinical isolates, vs its achievable concentrations in the human respiratory tract and comparison to ribavirin

“…These strain‐specific differences are small and are unlikely to affect the activity of MDT‐637 given the high achievable respiratory tract concentration. Similar RSV strain differences in fusion inhibitor activity have been previously reported …”

The Drug–Drug Interaction Profile of Presatovir

“…Presatovir (previously GS‐5806) is a novel, orally administered RSV fusion inhibitor that interferes with the viral fusion process, thereby inhibiting entry into the host cell . The antiviral efficacy of presatovir has been demonstrated in both preclinical and clinical studies .…”

“…Presatovir (previously GS‐5806) is a novel, orally administered RSV fusion inhibitor that interferes with the viral fusion process, thereby inhibiting entry into the host cell . The antiviral efficacy of presatovir has been demonstrated in both preclinical and clinical studies . Presatovir exhibited potent in vitro activity against a broad range of RSV A and B clinical isolates; reduced viral load, respiration rates, and lung pathology in a bovine RSV model; and lowered viral loads and symptom scores in healthy RSV‐infected volunteers .…”

GS-5806 Inhibits Pre- to Postfusion Conformational Changes of the Respiratory Syncytial Virus Fusion Protein

“…An RSV F resistance variant that contains a threonine-to-alanine amino acid change at position 400 of the RSV F protein was selected in vitro (12). ⌬TM-RSV F T400A protein purified in the prefusion conformation was also triggered by low-ionic-strength buffer in a manner similar to that in the wild-type protein, but this process could not be inhibited by GS-5806.…”

“…RSV infects the respiratory tract of infants, young children, and immunocompromised adults, causing severe disease (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). GS-5806 is a small-molecule inhibitor of RSV replication that is active against a diverse collection of RSV A and RSV B clinical isolates, with a mean 50% effective concentration (EC 50 ) of 0.43 nM (12,13). GS-5806 blocks RSV fusion (F) protein-mediated cell-cell fusion, and mutations that confer drug resistance map to the RSV F gene, suggesting that the target of GS-5806 is the RSV F protein.…”