Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro

IF 12.7 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

ACS Central Science Pub Date : 2023-01-25 DOI:10.1021/acscentsci.2c01359

Ningke Hou, Lei Shuai, Lijing Zhang, Xuping Xie, Kaiming Tang, Yunkai Zhu, Yin Yu, Wenyi Zhang, Qiaozhu Tan, Gongxun Zhong, Zhiyuan Wen, Chong Wang, Xijun He, Hong Huo, Haishan Gao, You Xu, Jing Xue, Chen Peng, Jing Zou, Craig Schindewolf, Vineet Menachery, Wenji Su, Youlang Yuan, Zuyuan Shen, Rong Zhang, Shuofeng Yuan, Hongtao Yu, Pei-Yong Shi*, Zhigao Bu*, Jing Huang* and Qi Hu*,

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引用次数: 5

Abstract

The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, noncovalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC₅₀ values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment.

A novel oral noncovalent inhibitor of 3C-like protease, named WU-04, was developed as a promising drug candidate for COVID-19 treatment.

Abstract Image

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sars - cov - 23clpro高效非共价抑制剂的研制

3c样蛋白酶(3CLpro)是SARS-CoV-2和其他冠状病毒复制的必需酶，因此是冠状病毒药物开发的靶标。目前报道的冠状病毒3CLpro抑制剂几乎都是共价抑制剂。在这里，我们报道了特异性的，非共价3CLpro抑制剂的发展。其中最有效的WU-04能有效阻断SARS-CoV-2在人细胞中的复制，EC50值在10 nm范围内。WU-04还能高效抑制SARS-CoV和MERS-CoV的3CLpro，表明其是冠状病毒3CLpro的泛抑制剂。WU-04对K18-hACE2小鼠的抗sars - cov -2活性与口服相同剂量的PF-07321332 (Nirmatrelvir)相似。因此，WU-04是一种很有前途的冠状病毒治疗药物。一种新的口服非共价3c样蛋白酶抑制剂WU-04被开发出来，作为治疗COVID-19的有希望的候选药物。

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来源期刊

ACS Central Science Chemical Engineering-General Chemical Engineering

CiteScore

25.50

自引率

0.50%

发文量

194

审稿时长

10 weeks

期刊介绍： ACS Central Science publishes significant primary reports on research in chemistry and allied fields where chemical approaches are pivotal. As the first fully open-access journal by the American Chemical Society, it covers compelling and important contributions to the broad chemistry and scientific community. "Central science," a term popularized nearly 40 years ago, emphasizes chemistry's central role in connecting physical and life sciences, and fundamental sciences with applied disciplines like medicine and engineering. The journal focuses on exceptional quality articles, addressing advances in fundamental chemistry and interdisciplinary research.