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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\n              <jats:italic>in vitro<\/jats:italic>\n              and\n              <jats:italic>in vivo<\/jats:italic>\n              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\n              <jats:italic>in vitro<\/jats:italic>\n              and more pathogenic than the parental strain\n              <jats:italic>in vivo<\/jats:italic>\n              . The small molecule (2\n              <jats:italic>E<\/jats:italic>\n              ,2\u2032\n              <jats:italic>E<\/jats:italic>\n              )-\n              <jats:italic>N<\/jats:italic>\n              ,\n              <jats:italic>N<\/jats:italic>\n              \u2032-((1\n              <jats:italic>R<\/jats:italic>\n              ,2\n              <jats:italic>S<\/jats:italic>\n              ,3\n              <jats:italic>S<\/jats:italic>\n              )\u22123-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\n              <jats:italic>in vitro<\/jats:italic>\n              and\n              <jats:italic>in vivo<\/jats:italic>\n              infections of both wild-type RSV and the K394R variant. Mechanistically, CL-A3-7 significantly inhibited virus\u2013cell 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.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              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\n              <jats:italic>in vitro<\/jats:italic>\n              and\n              <jats:italic>in vivo<\/jats:italic>\n              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.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.01385-24","type":"journal-article","created":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T13:03:45Z","timestamp":1724159025000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":18,"title":["A new mechanism of respiratory syncytial virus entry inhibition by small-molecule to overcome K394R-associated resistance"],"prefix":"10.1128","volume":"15","author":[{"given":"Qiaoyun","family":"Song","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China"},{"name":"Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM &amp; New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China"},{"name":"Center for Bioactive Natural Molecules and Innovative Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyue","family":"Zhu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China"},{"name":"Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM &amp; New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manlan","family":"Qiu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China"},{"name":"Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM &amp; New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialiao","family":"Cai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China"},{"name":"Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM &amp; New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive 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