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A new mechanism of respiratory syncytial virus entry inhibition by small-molecule to overcome K394R-associated resistance.
Song, Qiaoyun; Zhu, Haoyue; Qiu, Manlan; Cai, Jialiao; Hu, Yun; Yang, Haixia; Rao, Shuwen; Li, Yaolan; Li, Manmei; Hu, Lijun; Wang, Shuqin; Hong, Jian; Ye, Wencai; Chen, Heru; Wang, Ying; Tang, Wei.
Afiliação
  • Song Q; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China.
  • Zhu H; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM & New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China.
  • Qiu M; Center for Bioactive Natural Molecules and Innovative Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China.
  • Cai J; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China.
  • Hu Y; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM & New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China.
  • Yang H; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China.
  • Rao S; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM & New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China.
  • Li Y; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China.
  • Li M; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM & New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China.
  • Hu L; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China.
  • Wang S; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM & New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China.
  • Hong J; Center for Bioactive Natural Molecules and Innovative Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China.
  • Ye W; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China.
  • Chen H; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM & New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China.
  • Wang Y; Center for Bioactive Natural Molecules and Innovative Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China.
  • Tang W; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China.
mBio ; 15(9): e0138524, 2024 Sep 11.
Article em En | MEDLINE | ID: mdl-39162560
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 (2E,2'E)-N,N'-((1R,2S,3S)-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-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 in vitro and in vivo 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Proteínas Virais de Fusão / Vírus Sincicial Respiratório Humano / Infecções por Vírus Respiratório Sincicial / Farmacorresistência Viral / Internalização do Vírus Limite: Animals / Female / Humans Idioma: En Revista: MBio Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Proteínas Virais de Fusão / Vírus Sincicial Respiratório Humano / Infecções por Vírus Respiratório Sincicial / Farmacorresistência Viral / Internalização do Vírus Limite: Animals / Female / Humans Idioma: En Revista: MBio Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China País de publicação: Estados Unidos