Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19
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 i...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54462-0 |
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| author | 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 Jinsai Shang |
| author_facet | 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 Jinsai Shang |
| author_sort | Yongzhi Lu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-5462387096af431981c9861019175559 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-5462387096af431981c98610191755592025-01-26T12:40:15ZengNature PortfolioNature Communications2041-17232024-11-0115111610.1038/s41467-024-54462-0Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19Yongzhi Lu0Qi Yang1Ting Ran2Guihua Zhang3Wenqi Li4Peiqi Zhou5Jielin Tang6Minxian Dai7Jinpeng Zhong8Hua Chen9Pan He10Anqi Zhou11Bao Xue12Jiayi Chen13Jiyun Zhang14Sidi Yang15Kunzhong Wu16Xinyu Wu17Miru Tang18Wei K. Zhang19Deyin Guo20Xinwen Chen21Hongming Chen22Jinsai Shang23Guangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratorySchool of Basic Medical Sciences, Guangzhou Laboratory, Guangzhou Medical UniversityGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryAbstract 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.https://doi.org/10.1038/s41467-024-54462-0 |
| spellingShingle | 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 Jinsai Shang Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19 Nature Communications |
| title | Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19 |
| title_full | Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19 |
| title_fullStr | Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19 |
| title_full_unstemmed | Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19 |
| title_short | Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19 |
| title_sort | discovery of orally bioavailable sars cov 2 papain like protease inhibitor as a potential treatment for covid 19 |
| url | https://doi.org/10.1038/s41467-024-54462-0 |
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