广告
化学
聚合酶
RNA聚合酶
甲型流感病毒
病毒学
病毒
核糖核酸
计算生物学
生物化学
体外
酶
基因
生物
作者
Anna Bonomini,Tommaso Felicetti,Martina Pacetti,Chiara Bertagnin,Alice Coletti,Federica Giammarino,Marta De Angelis,Federica Poggialini,Roberto Pellicciari,Stefano Sabatini,Beatrice Mercorelli,Lucia Nencioni,Ilaria Vicenti,Elena Dreassi,Violetta Cecchetti,Oriana Tabarrini,Arianna Loregian,Serena Massari
标识
DOI:10.1016/j.ejmech.2024.116737
摘要
Influenza viruses (IV) are single-stranded RNA viruses with a negative-sense genome and have the potential to cause pandemics. While vaccines exist for influenza, their protection is only partial. Additionally, there is only a limited number of approved anti-IV drugs, which are associated to emergence of drug resistance. To address these issues, for years we have focused on the development of small-molecules that can interfere with the heterodimerization of PA and PB1 subunits of the IV RNA-dependent RNA polymerase (RdRP). In this study, starting from a cycloheptathiophene-3-carboxamide compound that we recently identified, we performed iterative cycles of medicinal chemistry optimization that led to the identification of compounds 43 and 45 with activity in the nanomolar range against circulating A and B strains of IV. Mechanistic studies demonstrated the ability of 43 and 45 to interfere with viral RdRP activity by disrupting PA-PB1 subunits heterodimerization and to bind to the PA C-terminal domain through biophysical assays. Most important, ADME studies of 45 also showed an improvement in the pharmacokinetic profile with respect to the starting hit.
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