核酸内切酶
化学
对接(动物)
甲型流感病毒
病毒
酶
生物化学
病毒学
立体化学
生物
医学
护理部
作者
Yixian Liao,Yilu Ye,Sumei Li,Yilian Zhuang,Liye Chen,Jianxin Chen,Zi‐Ning Cui,Lijian Huo,Shuwen Liu,Gaopeng Song
标识
DOI:10.1016/j.ejmech.2020.112048
摘要
Currently, influenza PAN endonuclease has become an attractive target for development of new drugs to treat influenza infections. Herein we report the discovery of new PAN endonuclease inhibitors derived from a chelating agent dopamine moiety. A series of dopamine amide derivatives and their conformationally constrained 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based analogs were elaborated and assayed against influenza virus A/WSN/33 (H1N1). Most compounds exhibited moderate to excellent antiviral activities, generating a preliminary SARs. Among them, compounds 14 and 19 showed stronger anti-IAV activity compared with the reference Peramivir. Moreover, 14 and 19 demonstrated a concentration-dependent inhibition of PAN endonuclease based on both FRET assay and SPR assay. Docking studies were also performed to elucidate the binding mode of 14 and 19 with the PAN protein and to identify amino acids involved in their mechanism of action, which were well consistent with the biological data. This finding was beneficial to laying the foundation for the rational development of more effective PAN endonuclease inhibitors.
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