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

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; Qi Hu

doi:10.1021/acscentsci.2c01359

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

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 SchindewolfVineet Menachery, Wenji Su, Youlang Yuan, Zuyuan Shen, Rong Zhang, Shuofeng Yuan, Hongtao Yu, Pei Yong Shi, Zhigao Bu, Jing Huang, Qi Hu

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	217-227
Number of pages	11
Journal	ACS Central Science
Volume	9
Issue number	2
DOIs	https://doi.org/10.1021/acscentsci.2c01359
State	Published - Feb 22 2023

ASJC Scopus subject areas

General Chemistry
General Chemical Engineering

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Hou, N, Shuai, L, Zhang, L, Xie, X, Tang, K, Zhu, Y, Yu, Y, Zhang, W, Tan, Q, Zhong, G, Wen, Z, Wang, C, He, X, Huo, H, Gao, H, Xu, Y, Xue, J, Peng, C, Zou, J, Schindewolf, C, Menachery, V, Su, W, Yuan, Y, Shen, Z, Zhang, R, Yuan, S, Yu, H, Shi, PY, Bu, Z, Huang, J & Hu, Q 2023, 'Development of Highly Potent Noncovalent Inhibitors of SARS-CoV‑2 3CLpro', ACS Central Science, vol. 9, no. 2, pp. 217-227. https://doi.org/10.1021/acscentsci.2c01359

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title = "Development of Highly Potent Noncovalent Inhibitors of SARS-CoV‑2 3CLpro",

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.",

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

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doi = "10.1021/acscentsci.2c01359",

language = "English (US)",

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T1 - Development of Highly Potent Noncovalent Inhibitors of SARS-CoV‑2 3CLpro

AU - Hou, Ningke

AU - Shuai, Lei

AU - Zhang, Lijing

AU - Xie, Xuping

AU - Tang, Kaiming

AU - Zhu, Yunkai

AU - Yu, Yin

AU - Zhang, Wenyi

AU - Tan, Qiaozhu

AU - Zhong, Gongxun

AU - Wen, Zhiyuan

AU - Wang, Chong

AU - He, Xijun

AU - Huo, Hong

AU - Gao, Haishan

AU - Xu, You

AU - Xue, Jing

AU - Peng, Chen

AU - Zou, Jing

AU - Schindewolf, Craig

AU - Menachery, Vineet

AU - Su, Wenji

AU - Yuan, Youlang

AU - Shen, Zuyuan

AU - Zhang, Rong

AU - Yuan, Shuofeng

AU - Yu, Hongtao

AU - Shi, Pei Yong

AU - Bu, Zhigao

AU - Huang, Jing

AU - Hu, Qi

PY - 2023/2/22

Y1 - 2023/2/22

N2 - 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.

AB - 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.

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

Abstract

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