A new mechanism of respiratory syncytial virus entry inhibition by small-molecule to overcome K394R-associated resistance

作者：Qiao‐Yun Song, Haoyue Zhu, Manlan Qiu, Jialiao Cai, Yun Hu, Haixia Yang, Shuwen Rao, Yao-Lan Li, Man‐Mei Li, Lijun Hu, Shuqin Wang, Jian Hong, Wen‐Cai Ye, Heru Chen, Ying Wang, Wei Tang · 发表于：mBio · 年份：2024 · DOI：10.1128/mbio.01385-24 · 被引用次数：18 · 研究领域：Respiratory viral infections research、Viral gastroenteritis research and epidemiology、Pneumonia and Respiratory Infections

ABSTRACT Infection with respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract disease in young children and older people. Despite intensive efforts over the past few decades, no direct-acting small-molecule agents against RSV are available. Most small-molecule candidates targeting the RSV fusion (F) protein pose a considerable risk of inducing drug-resistant mutations. Here, we explored the in vitro and in vivo virological properties of the K394R variant, a cross-resistant mutant capable of evading multiple RSV fusion inhibitors. Our results demonstrated that the K394R variant is highly fusogenic in vitro and more pathogenic than the parental strain in vivo . The small molecule (2 E ,2′ E )- N , N ′-((1 R ,2 S ,3 S )−3-hydroxycyclohexane-1,2-diyl)bis(3-(2-bromo-4-fluorophenyl) acrylamide) (CL-A3-7), a structurally optimized compound derived from a natural caffeoylquinic acid derivative, substantially reduced in vitro and in vivo infections of both wild-type RSV and the K394R variant. Mechanistically, CL-A3-7 significantly inhibited virus–cell fusion during RSV entry by blocking the interaction between the viral F protein and the cellular insulin-like growth factor 1 receptor (IGF1R). Collectively, these results indicate severe disease risks caused by the K394R variant and reveal a new anti-RSV mechanism to overcome K394R-associated resistance. IMPORTANCE Respiratory syncytial virus (RSV) infection is a major public health concern, and many small-...