蛋白酵素
冠状病毒
蛋白酶
化学
高致病性
致病菌
2019年冠状病毒病(COVID-19)
病毒学
生物
病毒
酶
生物化学
细菌
医学
遗传学
疾病
病理
传染病(医学专业)
H5N1亚型流感病毒
作者
Yanru Zhou,Weiwei Wang,Pei Zeng,Jingwen Feng,Dongyang Li,Yue Jing,Jin Zhang,Xue Yin,Jian Li,Heyang Ye,Qisheng Wang
标识
DOI:10.1016/j.bbrc.2023.03.043
摘要
PF-07321332 and PF-07304814, inhibitors against SARS-CoV-2 developed by Pfizer, exhibit broad-spectrum inhibitory activity against the main protease (Mpro) from various coronaviruses. Structures of PF-07321332 or PF-07304814 in complex with Mpros of various coronaviruses reveal their inhibitory mechanisms against different Mpros. However, the structural information on the lower pathogenic coronavirus Mpro with PF-07321332 or PF-07304814 is currently scarce, which hinders our comprehensive understanding of the inhibitory mechanisms of these two inhibitors. Meanwhile, given that some immunocompromised individuals are still affected by low pathogenic coronaviruses, we determined the structures of lower pathogenic coronavirus HCoV-229E Mpro with PF-07321332 and PF-07304814, respectively, and analyzed and defined in detail the structural basis for the inhibition of HCoV-229E Mpro by both inhibitors. Further, we compared the crystal structures of multiple coronavirus Mpro complexes with PF-07321332 or PF-07304814 to illustrate the differences in the interaction of Mpros, and found that the inhibition mechanism of lower pathogenic coronavirus Mpro was more similar to that of moderately pathogenic coronaviruses. Our structural studies provide new insights into drug development for low pathogenic coronavirus Mpro, and provide theoretical basis for further optimization of both inhibitors to contain potential future coronaviruses.
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