File Download
There are no files associated with this item.
Links for fulltext
(May Require Subscription)
- Publisher Website: 10.1038/s41564-022-01119-7
- Scopus: eid_2-s2.0-85128836598
- PMID: 35477751
- WOS: WOS:000790292100012
Supplementary
- Citations:
- Appears in Collections:
Article: An orally available Mpro inhibitor is effective against wild-type SARS-CoV-2 and variants including Omicron
Title | An orally available Mpro inhibitor is effective against wild-type SARS-CoV-2 and variants including Omicron |
---|---|
Authors | Quan, Bao XueShuai, HuipingXia, An JieHou, YuxinZeng, RuiLiu, Xin LeiLin, Gui FengQiao, Jing XinLi, Wen PeiWang, Fa LuWang, KaiZhou, Ren JieYuen, Terrence Tsz TaiChen, Ming XinYoon, ChaeminWu, MingZhang, Shi YuHuang, ChongWang, Yi FeiYang, WeiTian, ChenyuLi, Wei MinWei, Yu QuanYuen, Kwok YungChan, Jasper Fuk WooLei, JianChu, HinYang, Shengyong |
Issue Date | 2022 |
Citation | Nature Microbiology, 2022, v. 7, n. 5, p. 716-725 How to Cite? |
Abstract | Emerging SARS-CoV-2 variants continue to cause waves of new infections globally. Developing effective antivirals against SARS-CoV-2 and its variants is an urgent task. The main protease (Mpro) of SARS-CoV-2 is an attractive drug target because of its central role in viral replication and its conservation among variants. We herein report a series of potent α-ketoamide-containing Mpro inhibitors obtained using the Ugi four-component reaction. The prioritized compound, Y180, showed an IC50 of 8.1 nM against SARS-CoV-2 Mpro and had oral bioavailability of 92.9%, 31.9% and 85.7% in mice, rats and dogs, respectively. Y180 protected against wild-type SARS-CoV-2, B.1.1.7 (Alpha), B.1.617.1 (Kappa) and P.3 (Theta), with EC50 of 11.4, 20.3, 34.4 and 23.7 nM, respectively. Oral treatment with Y180 displayed a remarkable antiviral potency and substantially ameliorated the virus-induced tissue damage in both nasal turbinate and lung of B.1.1.7-infected K18-human ACE2 (K18-hACE2) transgenic mice. Therapeutic treatment with Y180 improved the survival of mice from 0 to 44.4% (P = 0.0086) upon B.1.617.1 infection in the lethal infection model. Importantly, Y180 was also highly effective against the B.1.1.529 (Omicron) variant both in vitro and in vivo. Overall, our study provides a promising lead compound for oral drug development against SARS-CoV-2. |
Persistent Identifier | http://hdl.handle.net/10722/315396 |
ISI Accession Number ID |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Quan, Bao Xue | - |
dc.contributor.author | Shuai, Huiping | - |
dc.contributor.author | Xia, An Jie | - |
dc.contributor.author | Hou, Yuxin | - |
dc.contributor.author | Zeng, Rui | - |
dc.contributor.author | Liu, Xin Lei | - |
dc.contributor.author | Lin, Gui Feng | - |
dc.contributor.author | Qiao, Jing Xin | - |
dc.contributor.author | Li, Wen Pei | - |
dc.contributor.author | Wang, Fa Lu | - |
dc.contributor.author | Wang, Kai | - |
dc.contributor.author | Zhou, Ren Jie | - |
dc.contributor.author | Yuen, Terrence Tsz Tai | - |
dc.contributor.author | Chen, Ming Xin | - |
dc.contributor.author | Yoon, Chaemin | - |
dc.contributor.author | Wu, Ming | - |
dc.contributor.author | Zhang, Shi Yu | - |
dc.contributor.author | Huang, Chong | - |
dc.contributor.author | Wang, Yi Fei | - |
dc.contributor.author | Yang, Wei | - |
dc.contributor.author | Tian, Chenyu | - |
dc.contributor.author | Li, Wei Min | - |
dc.contributor.author | Wei, Yu Quan | - |
dc.contributor.author | Yuen, Kwok Yung | - |
dc.contributor.author | Chan, Jasper Fuk Woo | - |
dc.contributor.author | Lei, Jian | - |
dc.contributor.author | Chu, Hin | - |
dc.contributor.author | Yang, Shengyong | - |
dc.date.accessioned | 2022-08-05T10:18:44Z | - |
dc.date.available | 2022-08-05T10:18:44Z | - |
dc.date.issued | 2022 | - |
dc.identifier.citation | Nature Microbiology, 2022, v. 7, n. 5, p. 716-725 | - |
dc.identifier.uri | http://hdl.handle.net/10722/315396 | - |
dc.description.abstract | Emerging SARS-CoV-2 variants continue to cause waves of new infections globally. Developing effective antivirals against SARS-CoV-2 and its variants is an urgent task. The main protease (Mpro) of SARS-CoV-2 is an attractive drug target because of its central role in viral replication and its conservation among variants. We herein report a series of potent α-ketoamide-containing Mpro inhibitors obtained using the Ugi four-component reaction. The prioritized compound, Y180, showed an IC50 of 8.1 nM against SARS-CoV-2 Mpro and had oral bioavailability of 92.9%, 31.9% and 85.7% in mice, rats and dogs, respectively. Y180 protected against wild-type SARS-CoV-2, B.1.1.7 (Alpha), B.1.617.1 (Kappa) and P.3 (Theta), with EC50 of 11.4, 20.3, 34.4 and 23.7 nM, respectively. Oral treatment with Y180 displayed a remarkable antiviral potency and substantially ameliorated the virus-induced tissue damage in both nasal turbinate and lung of B.1.1.7-infected K18-human ACE2 (K18-hACE2) transgenic mice. Therapeutic treatment with Y180 improved the survival of mice from 0 to 44.4% (P = 0.0086) upon B.1.617.1 infection in the lethal infection model. Importantly, Y180 was also highly effective against the B.1.1.529 (Omicron) variant both in vitro and in vivo. Overall, our study provides a promising lead compound for oral drug development against SARS-CoV-2. | - |
dc.language | eng | - |
dc.relation.ispartof | Nature Microbiology | - |
dc.title | An orally available Mpro inhibitor is effective against wild-type SARS-CoV-2 and variants including Omicron | - |
dc.type | Article | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1038/s41564-022-01119-7 | - |
dc.identifier.pmid | 35477751 | - |
dc.identifier.scopus | eid_2-s2.0-85128836598 | - |
dc.identifier.volume | 7 | - |
dc.identifier.issue | 5 | - |
dc.identifier.spage | 716 | - |
dc.identifier.epage | 725 | - |
dc.identifier.eissn | 2058-5276 | - |
dc.identifier.isi | WOS:000790292100012 | - |