Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19
The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CL<sup>pro</sup>), and papain-like protease (PL<sup>pro</sup>) 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 3CL<sup>pro</sup> inhibitors. However, the mutations causing drug resistance have been observed in RdRp and 3CL<sup>pro</sup> 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 PL<sup>pro</sup> inhibitors with remarkable in vitro potency and in vivo PK properties. The co-crystal structures of PL<sup>pro</sup> 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 EC<sub>50</sub> ranging from 58.2 nM to 306.2 nM, but also inhibits HCoV-NL63 and HCoV-229E with EC<sub>50</sub> 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 PL<sup>pro</sup> inhibitors represent a promising SARS-CoV-2 therapy.
Authors
- Wei Kevin Zhang (ORCID: https://orcid.org/0000-0003-4960-6137)
- Jielin Tang (ORCID: https://orcid.org/0000-0002-4398-2927)
- Guihua Zhang (ORCID: https://orcid.org/0000-0002-3131-7081)
- Jiyun Zhang (ORCID: https://orcid.org/0000-0002-4101-9141)
- Sidi Yang (ORCID: https://orcid.org/0000-0003-0251-0162)
- Deyin Guo (ORCID: https://orcid.org/0000-0002-8297-0814)
- Ting Ran (ORCID: https://orcid.org/0000-0002-1387-4634)
- Minxian Dai
- Jinsai Shang (ORCID: https://orcid.org/0000-0001-8164-1544)
- Anqi Zhou (ORCID: https://orcid.org/0000-0001-9358-3054)
- Xinwen Chen (ORCID: https://orcid.org/0000-0002-4052-8155)
- Hua Chen (ORCID: https://orcid.org/0000-0003-3086-2317)
- Weifeng Li (ORCID: https://orcid.org/0000-0003-2495-3415)
- Jinpeng Zhong
- Jiayi Chen (ORCID: https://orcid.org/0000-0001-9325-5237)
- Qi Yang (ORCID: https://orcid.org/0009-0009-1648-4189)
- Hongming Chen (ORCID: https://orcid.org/0000-0002-8065-8333)
- Pan He (ORCID: https://orcid.org/0000-0002-2938-6619)
- Xue Bao (ORCID: https://orcid.org/0000-0002-5129-0728)
- Xinyu Wu (ORCID: https://orcid.org/0000-0002-9094-9951)
- Yongzhi Lu (ORCID: https://orcid.org/0000-0002-9985-8546)
- Peiqi Zhou
- Miru Tang
- Kunzhong Wu
Institutions
- Sun Yat-sen University (CN)
- Nankai University (CN)
- Guangzhou Experimental Station (CN)
- State Key Laboratory of Respiratory Disease (CN)
- Huazhong University of Science and Technology (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-23
- DOI
- https://doi.org/10.1038/s41467-024-54462-0
- Citations
- 26
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 10.11
Funders
- Vanderbilt University
- Salt Science Research Foundation
- National Natural Science Foundation of China
- Natural Science Foundation of Guangdong Province