Orally active fusion inhibitor of respiratory syncytial virus
Orally active fusion inhibitor of respiratory syncytial virus
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DOI：
10.1128/aac.48.2.413-422.2004
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发表时间：
2004-02-01
影响因子：
4.9
通讯作者：
Krystal, M
中科院分区：
文献类型：
--
作者：
Cianci, C;Yu, KL;Krystal, M
发现BMS-433771是体外呼吸道合胞病毒（RSV）复制的强效抑制剂。它对A组和B组病毒的多种实验室和临床分离株表现出优异的效力，平均50%有效浓度为20 nM。作用机制研究表明，BMS-433771在早期病毒进入阶段和晚期合胞体形成期间均抑制脂膜融合。在分离抗性病毒后，抗性被映射到融合蛋白的F1亚基中的一系列单个氨基酸突变。经口给药后，BMS-433771能够降低RSV感染小鼠肺中的病毒滴度。这类新的口服活性RSV融合抑制剂提供了临床开发的潜力。
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.