A Warhead Substitution Study on the Coronavirus Main Protease Inhibitor Nirmatrelvir

被引：32

作者：

Vankadara, Subramanyam ^{[1
]}

Dawson, Monique Danielle ^{[1
]}

Fong, Jia Yi ^{[1
]}

Oh, Qin Yao ^{[1
]}

Ang, Qi An ^{[1
]}

Liu, Boping ^{[1
]}

Chang, Hong Yun ^{[1
]}

Koh, Judice ^{[1
]}

Koh, Xiaoying ^{[1
]}

Tan, Qian Wen ^{[1
]}

Joy, Joma ^{[1
]}

Chia, Cheng San Brian ^{[1
]}

机构：

[1] Expt Drug Dev Ctr, Singapore 138670, Singapore

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2022年 / 13卷 / 08期

关键词：

SARS-CoV-2; COVID-19; 3CLpro; Mpro; nirmatrelvir; Paxlovid; STRUCTURE-BASED DESIGN; 3C PROTEASE; PEPTIDOMIMETIC INHIBITORS; BIOLOGICAL EVALUATION; COVALENT INHIBITORS; ANTIVIRAL ACTIVITY; SERINE-PROTEASE; HEPATITIS-C; POTENT; P3;

D O I：

10.1021/acsmedchemlett.2c00260

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The SARS-CoV-2 pandemic is currently causing an unprecedented global health emergency since its emergence in December 2019. In December 2021, the FDA granted emergency use authorization to nirmatrelvir, a SARS-CoV-2 main protease inhibitor, for treating infected patients. This peptidomimetic is designed with a nitrile warhead, which forms a covalent bond to the viral protease. Herein, we investigate nirmatrelvir analogs with different warheads and their inhibitory activities. In addition, antiviral activities against human alphacoronavirus 229E was also investigated along with a cell-based assay. We discovered that the hydroxymethylketone and ketobenzothiazole warheads were equipotent to the nitrile warhead, suggesting that these analogs can also be used for treating coronavirus infections.

引用

页码：1345 / 1350

页数：6

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