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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.

SUBMITTER: Hou N

PROVIDER: S-EPMC9885526 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

Hou Ningke N Shuai Lei L Zhang Lijing L Xie Xuping X Tang Kaiming K Zhu Yunkai Y Yu Yin Y Zhang Wenyi W Tan Qiaozhu Q Zhong Gongxun G Wen Zhiyuan Z Wang Chong C He Xijun X Huo Hong H Gao Haishan H Xu You Y Xue Jing J Peng Chen C Zou Jing J Schindewolf Craig C Menachery Vineet V Su Wenji W Yuan Youlang Y Shen Zuyuan Z Zhang Rong R Yuan Shuofeng S Yu Hongtao H Shi Pei-Yong PY Bu Zhigao Z Huang Jing J Hu Qi Q

ACS central science 20230125 2

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 EC<sub>50</sub> values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS ...[more]

PMID: 36844503

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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) are zoonotic betacoronaviruses that continue to have a significant impact on public health. Timely development and introduction of vaccines and antivirals against SARS-CoV-2 into the clinic have substantially mitigated the burden of COVID-19. However, a limited or lacking therapeutic arsenal for SARS-CoV-2 and MERS-CoV infections, respectively, calls for an expanded and diversified portfolio of antivirals against these coronavirus infections. In this report, we examined the efficacy of two potent 3CLpro inhibitors, 5d and 11d, in fatal animal models of SARS-CoV-2 and MERS-CoV to demonstrate their broad-spectrum activity against both viral infections. These compounds significantly increased the survival of mice in both models when treatment started 1 day post infection compared to no treatment which led to 100% fatality. Especially, the treatment with compound 11d resulted in 80% and 90% survival in SARS-CoV-2 and MERS-CoV-infected mice, respectively. Amelioration of lung viral load and histopathological changes in treated mice correlated well with improved survival in both infection models. Furthermore, compound 11d exhibited significant antiviral activities in K18-hACE2 mice infected with SARS-CoV-2 Omicron subvariant XBB.1.16. The results suggest that these are promising candidates for further development as broad-spectrum direct-acting antivirals against highly virulent human coronaviruses.IMPORTANCEHuman coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) continue to have a significant impact on public health. A limited or lacking therapeutic arsenal for SARS-CoV-2 and MERS-CoV infections calls for an expanded and diversified portfolio of antivirals against these coronavirus infections. We have previously reported a series of small-molecule 3C-like protease (3CLpro) inhibitors against human coronaviruses. In this report, we demonstrated the in vivo efficacy of 3CLpro inhibitors for their broad-spectrum activity against both SARS-CoV-2 and MERS-CoV infections using the fatal animal models. The results suggest that these are promising candidates for further development as broad-spectrum direct-acting antivirals against highly virulent human coronaviruses.

Dataset Information

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

Publications

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

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