A new mechanism of respiratory syncytial virus entry inhibition by small-molecule to overcome K394R-associated resistance
Respiratory syncytial virus (RSV) infection is a major public health concern, and many small-molecule candidates targeting the viral fusion (F) protein are associated with a considerable risk of inducing drug-resistant mutations. This study investigated virological features of the K394R variant, a mutant strain conferring resistance to multiple RSV fusion inhibitors. Our results demonstrated that the K394R variant is highly fusogenic in cell cultures and more pathogenic than the parental strain in mice. The small-molecule inhibitor CL-A3-7 substantially reduced <i>in vitro</i> and <i>in vivo</i> infections of both wild-type RSV and the K394R variant by blocking the interaction of viral F protein with its cellular receptor, showing a new mechanism of action for small-molecules to inhibit RSV infection and overcome K394R-associated resistance.
Authors
- Lijun Hu (ORCID: https://orcid.org/0000-0002-3019-6548)
- Heru Chen (ORCID: https://orcid.org/0000-0001-7076-3749)
- Jian Hong (ORCID: https://orcid.org/0000-0003-1084-3979)
- Shuwen Rao
- Haixia Yang (ORCID: https://orcid.org/0000-0002-4410-9257)
- Wen‐Cai Ye (ORCID: https://orcid.org/0000-0002-2810-1001)
- Man‐Mei Li (ORCID: https://orcid.org/0000-0003-2423-3119)
- Qiao‐Yun Song
- Jialiao Cai (ORCID: https://orcid.org/0009-0009-2491-3668)
- Yao-Lan Li
- Shuqin Wang (ORCID: https://orcid.org/0000-0003-4873-1307)
- Ying Wang (ORCID: https://orcid.org/0000-0003-4524-1812)
- Wei Tang (ORCID: https://orcid.org/0000-0002-1990-4558)
- Haoyue Zhu
- Yun Hu
- M F Qiu
Institutions
- Jinan University (CN)
Publication Details
- Journal
- mBio
- Published
- 2024-08-20
- DOI
- https://doi.org/10.1128/mbio.01385-24
- Citations
- 11
- Primary Topic
- Respiratory viral infections research
- Type
- article
- Field-Weighted Citation Impact
- 4.25
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Guangdong Province
- Basic and Applied Basic Research Foundation of Guangdong Province