RFI-641, a Potent Respiratory Syncytial Virus Inhibitor

Abstract

Human respiratory syncytial virus (RSV), a paramyxovirus, is a major cause of acute upper and lower respiratory tract infections in infants, young children, and adults. RFI-641 is a novel anti-RSV agent with potent in vitro and in vivo activity. RFI-641 is active against both RSV type A and B strains. The viral specificity and the large therapeutic window of RFI-641 (>100-fold) indicate that the antiviral activity of the compound is not due to adverse effects on normal cells. The potent in vitro activity of RFI-641 can be translated to efficacy in vivo: RFI-641 is efficacious when administered prophylactically by the intranasal route in mice, cotton rats, and African green monkeys. RFI-641 is also efficacious when administered therapeutically (24 h postinfection) in the monkey model. Mechanism of action studies indicate that RFI-641 blocks viral F protein-mediated fusion and cell syncytium formation.Human respiratory syncytial virus (RSV), a member of the Paramyxoviridae family (18), is a major cause of acute upper and lower respiratory tract infections in infants, young children, and adults. Serological evidence indicates that approximately 95% of children have been exposed to RSV by 2 years of age, and 100% of children have been exposed by the time they reach adulthood (8). In a given year, around 91,000 infants are hospitalized with RSV infection in the United States. These infections are responsible for 40 to 50% of hospitalizations for pediatric bronchiolitis and 25% of hospitalizations for pediatric pneumonia (8,15). Since the immune response to RSV infection is not protective, RSV infections reoccur throughout adulthood. In adults and older children, RSV infection has been associated with upper respiratory infection, tracheobronchitis, and otitis media. However, RSV in the institutionalized elderly can be more serious and is characterized by severe pneumonia and mortality rates of up to 20 and 78%, respectively (5, 6). Adults with a previous history of heart or lung conditions are at a high risk for RSV infection. The infection has been linked to exacerbation of patients with chronic obstructive pulmonary disease. Significant mortality has been observed in immunocompromised patients, particularly those undergoing bone marrow transplantation. Regular outbreaks of RSV are well characterized and predictable, occurring between October and May each year with peak occurrences in January and February. Ribavirin is the only commercially available agent used to treat RSV infection (2). The utilization of ribavirin is limited due to efficacy and toxicity concerns as well as the very long treatment regimen required for its delivery by aerosol inhalation (19). Protective antibodies (14, 27), indicated for prophylaxis in high-risk children, are administered intravenously (RespiGam) or intramuscularly (Synagis). A number of small-molecule inhibitors of RSV have been identified, but to date none are clinically approved (7, 23). RFI-641 is the result of a chemical optimization of CL387626 (1, 4, 28), a compound that inhi...

Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model

“…The results presented here for TMC353121 in therapeutic regimens (study 2; table 1) demonstrate that the drug is able to reduce viral replication when administered 2 days after RSV challenge, confirming that sustained viral replication does occur in this murine model and can be inhibited even by delayed drug administration. In comparison, other F protein fusion inhibitors, such as BMS-433771 and RFI-641, were not effective when used therapeutically in the murine model [13,26], although RFI-641 showed efficacy in the African Green Monkey when administered in this manner [27]. …”

Animal Pneumoviruses: Molecular Genetics and Pathogenesis

“…Peptides derived from epitopes of the hRSV fusion or F protein blocked hRSV-induced syncytium formation at concentrations as low as 0.015 M (226). Small-molecule hRSV-specific fusion inhibitors have neutralizing activity against A and B group hRSV isolates in vitro and in vivo via blockade of cell-cell fusion (179,258,272), while a benzodithiin compound has demonstrated ability to interfere with intracellular processing of the hRSV fusion protein, thereby resulting in decreased infectivity (333). Other agents reported to have anti-hRSV activity have included crude plant protein extracts (3), some forms of superoxide dismutase (384), an L-aspartate transcarbamoylase inhibitor (383), eosinophil-derived neurotoxin, a potent RNase (87), and lovastatin (144).…”

Orally Active Fusion Inhibitor of Respiratory Syncytial Virus

“…Recently, a number of small-molecule inhibitors of RSV infection in cell culture have been described (27,33,41,60; K. Andries et al, Abstr. 40th Intersci.…”