Development of highly potent non-covalent inhibitors of SARS-CoV-2 3CLpro

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, P.-Y.; Bu, Z.; Huang, J.; Hu, Q.

doi:10.1101/2022.08.10.503531

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bioRxiv · 10.1101/2022.08.10.503531

Development of highly potent non-covalent inhibitors of SARS-CoV-2 3CLpro

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Abstract

The SARS-CoV-2 virus is the causal agent of the ongoing pandemic of coronavirus disease 2019 (COVID-19). There is an urgent need for potent, specific antiviral compounds against SARS-CoV-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, non-covalent 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. One-Sentence SummaryA oral non-covalent inhibitor of 3C-like protease effectively inhibits SARS-CoV-2 replication.

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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, P.-Y., Bu, Z., Huang, J., Hu, Q.. 2022-08-11. Development of highly potent non-covalent inhibitors of SARS-CoV-2 3CLpro. https://doi.org/10.1101/2022.08.10.503531

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