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Orally Active Fusion Inhibitor of Respiratory Syncytial Virus

2004; American Society for Microbiology; Volume: 48; Issue: 2 Linguagem: Inglês

10.1128/aac.48.2.413-422.2004

1098-6596

Christopher Cianci, Kuo‐Long Yu, Keith D. Combrink, Ny Sin, Bradley C. Pearce, Alan Wang, Rita L. Civiello, Stacey Voss, Guangxiang Luo, Kathy Kadow, Eugene V. Genovesi, Brian L. Venables, H. Belgin Gülgeze, Ashok K. Trehan, Jennifer James, Lucinda Lamb, Ivette Medina, Julia Roach, Zheng Yang, Lisa Zadjura, Richard J. Colonno, Junius M. Clark, Nicholas A. Meanwell, Mark Krystal,

Virology and Viral Diseases

ABSTRACT BMS-433771 was found to be a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. It exhibited excellent potency against multiple laboratory and clinical isolates of both group A and B viruses, with an average 50% effective concentration of 20 nM. Mechanism-of-action studies demonstrated that BMS-433771 inhibits the fusion of lipid membranes during both the early virus entry stage and late-stage syncytium formation. After isolation of resistant viruses, resistance was mapped to a series of single amino acid mutations in the F1 subunit of the fusion protein. Upon oral administration, BMS-433771 was able to reduce viral titers in the lungs of mice infected with RSV. This new class of orally active RSV fusion inhibitors offers potential for clinical development.