RSV604, a Novel Inhibitor of Respiratory Syncytial Virus Replication

Abstract

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections worldwide, yet no effective vaccine or antiviral treatment is available. Here we report the discovery and initial development of RSV604, a novel benzodiazepine with submicromolar anti-RSV activity. It proved to be equipotent against all clinical isolates tested of both the A and B subtypes of the virus. The compound has a low rate of in vitro resistance development. Sequencing revealed that the resistant virus had mutations within the nucleocapsid protein. This is a novel mechanism of action for anti-RSV compounds. In a three-dimensional human airway epithelial cell model, RSV604 was able to pass from the basolateral side of the epithelium effectively to inhibit virus replication after mucosal inoculation. RSV604, which is currently in phase II clinical trials, represents the first in a new class of RSV inhibitors and may have significant potential for the effective treatment of RSV disease.Human respiratory syncytial virus (RSV) is the most important respiratory pathogen that causes lower respiratory tract infections, such as bronchiolitis and pneumonia, in infants and young children, resulting in up to 125,000 hospitalizations annually in the United States (3). The infants most at risk of severe disease are those under 6 weeks of age, those with bronchopulmonary dysplasia, congenital heart disease, or immunodeficiency, and those born prematurely. Hospital admission rates for these groups range between 5% and 30% (20,25). The mortality rate among children admitted to hospital is approximately 3% for those with heart and lung problems and up to 1% for those without these risk factors (11,25). In adults and the elderly, RSV pneumonia is increasingly recognized as a significant cause of morbidity and mortality, being associated with more than 17,000 deaths annually between 1991 and 1998 (9, 22). Among the hospitalized elderly, mortality can be as high as 10 to 20%, and among severely immunocompromised patients with RSV pneumonia, it can be on the order of 50 to 70% (10). There is therefore an urgent and unmet medical need for novel therapies to deal with infections caused by this virus.The development of new therapeutics for RSV was recently reviewed (17,19). Although research into the prevention and treatment of RSV infection has been ongoing for almost 40 years, vaccine development is difficult (8, 13), and to date, there is no clinically approved vaccine. The development of RSV vaccines for use in young infants has been complicated by reduced immune responses in this age group due to immunologic immaturity and the immunosuppressive effects of maternal antibodies. Passive immunization with the monoclonal antibody palivizumab (Synagis) has provided about 50% protection to high-risk children (21). These include infants born prematurely and those with congenital conditions. Because the antibody has to be given prophylactically and treatment is very expensive, its use is limited mainly to developed countries. The effect...

The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment

“…Several direct-acting, small-molecule inhibitors targeting different steps of the RSV life cycle were tested, including TMC-353121, an entry inhibitor targeting the RSV fusion protein (13); RSV-604, an early postentry inhibitor binding a conserved region of the nucleocapsid protein (14,15); YM-53403, an inhibitor targeting the RSV polymerase in variable region 2 (16); and BI-D, an inhibitor targeting the RSV polymerase in domain V (17). The mechanisms of inhibition by RSV-604 and YM-53403…”

The Prophylaxis and Treatment with Antiviral Agents of Respiratory Syncytial Virus Infections

“…Two compounds with good antiviral potency were identified (compound 5: 50% inhibitory concentration [IC 50 ] ~110 nM; compound 6: IC 50 ~130 nM; Figure 3). Analogues of compound 5 displayed comparable potency (IC 50 46-74 nM). Detailed studies of the two lead compounds suggested that they interfered with viral fusion.…”

“…Antiviral potency was returned to the template by combining this modification with C4 substitution to yield TMC353121 ( Figure 2). The compound had good activity against a range of RSV strains (50% effective concentrations [EC 50 ] 500 nM-30 pM) and a plasma half life between 4 and 24 h but still possessed a large volume of distribution (79 l) and poor oral availability. When dosed at 10 mg/kg in the cotton rat model it showed 0.4 log reduction of virus load orally and 1.2 log reduction via the intravenous route.…”

“…Structural modifications to this compound showed that the unsubstituted benzodiazepine template was optimal for antiviral activity and SAR studies led to the identification of the ortho-fluorophenyl urea as the best candidate to proceed into the clinic (RSV604; Figure 5). The compound (IC 50 ~600 nM) is equipotent against both A-and B-strains of RSV and is also active against clinical isolates [50]. Generation of mutant viruses, using excess compound during viral replication, produced isolates that were 40-fold less sensitive to RSV604 compared with wildtype virus.…”

Treatment of Respiratory Syncytial Virus Infection: Past, Present and Future

“…RSV-604 (Arrow Therapeutics), an oral benzodiazepine with submicromolar potency against RSV A and B subfamilies (Chapman et al, 2007), is being developed in collaboration with Novartis. The safety and efficacy of this compound was tested in a multi-center trial that included RSV-infected adult bone marrow transplant patients.…”