Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19

Yongzhi Lu, Qi Yang, Ting Ran, Guihua Zhang, Wenqi Li, Peiqi Zhou, Jielin Tang, Minxian Dai, Jinpeng Zhong, Hua Chen, Pan He, Anqi Zhou, Bao Xue, Jiayi Chen, Jiyun Zhang, Sidi Yang, Kunzhong Wu, Xinyu Wu, Miru Tang, Wei K. Zhang, Deyin Guo, Xinwen Chen (), Hongming Chen () and Jinsai Shang ()
Additional contact information
Yongzhi Lu: Guangzhou National Laboratory
Qi Yang: Guangzhou National Laboratory
Ting Ran: Guangzhou National Laboratory
Guihua Zhang: Guangzhou National Laboratory
Wenqi Li: Guangzhou National Laboratory
Peiqi Zhou: Guangzhou National Laboratory
Jielin Tang: Guangzhou National Laboratory
Minxian Dai: Guangzhou National Laboratory
Jinpeng Zhong: Guangzhou National Laboratory
Hua Chen: Guangzhou National Laboratory
Pan He: Guangzhou National Laboratory
Anqi Zhou: Guangzhou Medical University
Bao Xue: Guangzhou National Laboratory
Jiayi Chen: Guangzhou National Laboratory
Jiyun Zhang: Guangzhou National Laboratory
Sidi Yang: Guangzhou National Laboratory
Kunzhong Wu: Guangzhou National Laboratory
Xinyu Wu: Guangzhou National Laboratory
Miru Tang: Guangzhou National Laboratory
Wei K. Zhang: Guangzhou National Laboratory
Deyin Guo: Guangzhou National Laboratory
Xinwen Chen: Guangzhou National Laboratory
Hongming Chen: Guangzhou National Laboratory
Jinsai Shang: Guangzhou National Laboratory

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CLpro), and papain-like protease (PLpro) are pivotal components in the viral life cycle of SARS-CoV-2, presenting as promising therapeutic targets. Currently, all FDA-approved antiviral drugs against SARS-CoV-2 are RdRp or 3CLpro inhibitors. However, the mutations causing drug resistance have been observed in RdRp and 3CLpro from SARS-CoV-2, which makes it necessary to develop antivirals with novel mechanisms. Through the application of a structure-based drug design (SBDD) approach, we discover a series of novel potent non-covalent PLpro inhibitors with remarkable in vitro potency and in vivo PK properties. The co-crystal structures of PLpro with lead compounds reveal that the residues D164 and Q269 around the S2 site are critical for improving the inhibitor’s potency. The lead compound GZNL-P36 not only inhibits SARS-CoV-2 and its variants at the cellular level with EC50 ranging from 58.2 nM to 306.2 nM, but also inhibits HCoV-NL63 and HCoV-229E with EC50 of 81.6 nM and 2.66 μM, respectively. Oral administration of the GZNL-P36 results in significantly improved survival and notable reductions in lung viral loads and lesions in SARS-CoV-2 infection mouse model, consistent with RNA-seq data analysis. Our results indicate that PLpro inhibitors represent a promising SARS-CoV-2 therapy.

Date: 2024
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DOI: 10.1038/s41467-024-54462-0

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