Oral Efficacy of a Respiratory Syncytial Virus Inhibitor in Rodent Models of Infection

Abstract

). In this report, the in vivo efficacy of BMS-433771 against RSV was further examined in the BALB/c mouse and cotton rat host models of infection. By using the Long strain of RSV, prophylactic efficacy via oral dosing was observed in both animal models. A single oral dose, administered 1 h prior to intranasal RSV inoculation, was as effective against infection as a 4-day b.i.d. dosing regimen in which the first oral dose was given 1 h prior to virus inoculation. Results of dose titration experiments suggested that RSV infection was more sensitive to inhibition by BMS-433771 treatment in the BALB/c mouse host than in the cotton rat. This was reflected by the pharmacokinetic and pharmacodynamic analysis of the efficacy data, where the area under the concentration-time curve required to achieve 50% of the maximum response was ϳ7.5-fold less for mice than for cotton rats. Inhibition of RSV by BMS-433771 in the mouse is the result of F1-mediated inhibition, as shown by the fact that a virus selected for resistance to BMS-433771 in vitro and containing a single amino acid change in the F1 region was also refractory to treatment in the mouse host. BMS-433771 efficacy against RSV infection was also demonstrated for mice that were chemically immunosuppressed by cyclophosphamide treatment, indicating that compound inhibition of the virus did not require an active host immune response.

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]. …”

“…The F (fusion) protein is crucial in this process and thus plays a critical role in establishing an infection. Several small molecule inhibitors of the fusion process have been identified [12][13][14][15][16][17], but most were discontinued for scientific or strategic reasons [18].…”

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

“…There are a number of animal models available for studying RSV, including primates, cows, cotton rats, and mice, each with its own set of advantages and disadvantages (52). In terms of rodents, we chose to use the cotton rat, because they have been shown to be at least 50-fold, and as much as 1,000-fold, more permissive than mouse strains for RSV (23), with the virus replicating in the nasal epithelium and bronchiolar epithelium of the animal (53). Because the in vitro antiviral effect of CAD phenocopies that of DHODH (the rate-limiting step), we chose to profile DHODH inhibition in the cotton rat model.…”

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

“…In addition, rodent models were used to assess the in vivo activity of BMS-433771 after oral administration. The maximum effect observed was > 1 log 10 reduction in viral load at doses of ≥ 5mg/kg in BALB/c mice and ≥ 50 mg/kg in cotton rats (Cianci et al, 2004a). …”