Discovery of potent SARS-CoV-2 nsp3 macrodomain inhibitors uncovers lack of translation to cellular antiviral response Alpha A. Lee 1,2* , Isabelle Amick 1,2 , Jasmin C. Aschenbrenner 1,3,8 , Haim M. Barr 1,4 , Jared Benjamin 1,5 , Alexander Brandis 1,9 , Galit Cohen 4 , Randy Diaz-Tapia 1,5 , Shirly Duberstein 1.4 , Jessica Dixon 1,7 , David Cousins 1,6 , Michael Fairhead 1,7 , Daren Fearon 1,3,8 , James Frick 1,2 , James Gayvert 1,2 , Andre S. Godoy 1,10 , Ed J. Griffin 1,6 , Kilian Huber 1,7 , Lizbé Koekemoer 1,7 , Noa Lahav 1,4 , Peter G. Marples 1,3,8,Briana L. McGovern 1,5,Tevie Mehlman 1,9,Matthew C. Robinson 1,2,Usha Singh 1,7,Tamas Szommer 1,7,Charles W.E.Tomlinson 1,3,8,Thomas Vargo 1,2,Frank Von Delft 1,3,7,8,Siyi Wang 1.7,Kris White 1,5,Eleanor Williams 1,7,Max Winokan 1,3,8
NSP3(NSP3MD)的大域在甲虫病毒中高度保守,而Chikungunya病毒(CHIKV)NSP3MD的ADP-核糖基水合酶活性对于Chikv病毒复制和毒力至关重要。迄今已确定针对CHIKV NSP3的小分子药物。在这里,我们报告了与NSP3MD结合的小片段,这些片段实际上是通过筛选片段和X射线晶体学来解决的。这些鉴定出的片段具有相似的支架,2-吡啶酮-4-羧酸,并特别结合了NSP3MD的ADP-核糖结合位点。Among the fragments, 2-oxo-5,6-benzo- pyrimidine-4-carboxylic acid showed anti-CHIKV activity with an IC 50 of 23 μ M. Our frag- ment-based drug discovery approach provides valuable information to further develop a specific and potent nsP3 inhibitor of CHIKV viral replication based on the 2-pyrimidone-4- carboxylic acid scaffold.表明,这种嘧啶支架也可以与其他α病毒和冠状病毒的大域结合,因此具有潜在的抗病毒活性。