tetano
Editor, Senior Moderator
Nat Commun
. 2024 Nov 23;15(1):10169.
doi: 10.1038/s41467-024-54462-0. Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19
Yongzhi Lu[SUP] #[/SUP][SUP] 1 2 [/SUP], Qi Yang[SUP] #[/SUP][SUP] 1 3 [/SUP], Ting Ran[SUP] #[/SUP][SUP] 1 [/SUP], Guihua Zhang[SUP] 1 [/SUP], Wenqi Li[SUP] 1 4 [/SUP], Peiqi Zhou[SUP] 1 [/SUP], Jielin Tang[SUP] 1 [/SUP], Minxian Dai[SUP] 1 [/SUP], Jinpeng Zhong[SUP] 1 [/SUP], Hua Chen[SUP] 1 [/SUP], Pan He[SUP] 1 [/SUP], Anqi Zhou[SUP] 2 [/SUP], Bao Xue[SUP] 1 [/SUP], Jiayi Chen[SUP] 1 5 [/SUP], Jiyun Zhang[SUP] 1 5 [/SUP], Sidi Yang[SUP] 1 [/SUP], Kunzhong Wu[SUP] 1 6 [/SUP], Xinyu Wu[SUP] 1 [/SUP], Miru Tang[SUP] 1 [/SUP], Wei K Zhang[SUP] 1 [/SUP], Deyin Guo[SUP] 1 3 [/SUP], Xinwen Chen[SUP] 7 8 [/SUP], Hongming Chen[SUP] 9 10 [/SUP], Jinsai Shang[SUP] 11 12 [/SUP]
Affiliations
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.
. 2024 Nov 23;15(1):10169.
doi: 10.1038/s41467-024-54462-0. Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19
Yongzhi Lu[SUP] #[/SUP][SUP] 1 2 [/SUP], Qi Yang[SUP] #[/SUP][SUP] 1 3 [/SUP], Ting Ran[SUP] #[/SUP][SUP] 1 [/SUP], Guihua Zhang[SUP] 1 [/SUP], Wenqi Li[SUP] 1 4 [/SUP], Peiqi Zhou[SUP] 1 [/SUP], Jielin Tang[SUP] 1 [/SUP], Minxian Dai[SUP] 1 [/SUP], Jinpeng Zhong[SUP] 1 [/SUP], Hua Chen[SUP] 1 [/SUP], Pan He[SUP] 1 [/SUP], Anqi Zhou[SUP] 2 [/SUP], Bao Xue[SUP] 1 [/SUP], Jiayi Chen[SUP] 1 5 [/SUP], Jiyun Zhang[SUP] 1 5 [/SUP], Sidi Yang[SUP] 1 [/SUP], Kunzhong Wu[SUP] 1 6 [/SUP], Xinyu Wu[SUP] 1 [/SUP], Miru Tang[SUP] 1 [/SUP], Wei K Zhang[SUP] 1 [/SUP], Deyin Guo[SUP] 1 3 [/SUP], Xinwen Chen[SUP] 7 8 [/SUP], Hongming Chen[SUP] 9 10 [/SUP], Jinsai Shang[SUP] 11 12 [/SUP]
Affiliations
- PMID: 39580525
- PMCID: PMC11585628
- DOI: 10.1038/s41467-024-54462-0
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.