An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis in vivo.

IF 7.5 1区 生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2024-11-05 DOI:10.1016/j.celrep.2024.114929
Nian E Zhou, Su Tang, Xuelin Bian, Maloy K Parai, Inna V Krieger, Armando Flores, Pradeep K Jaiswal, Radha Bam, Jeremy L Wood, Zhe Shi, Laura J Stevens, Trevor Scobey, Meghan V Diefenbacher, Fernando R Moreira, Thomas J Baric, Arjun Acharya, Joonyoung Shin, Manish M Rathi, Karen C Wolff, Laura Riva, Malina A Bakowski, Case W McNamara, Nicholas J Catanzaro, Rachel L Graham, David C Schultz, Sara Cherry, Yoshihiro Kawaoka, Peter J Halfmann, Ralph S Baric, Mark R Denison, Timothy P Sheahan, James C Sacchettini
{"title":"An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis in vivo.","authors":"Nian E Zhou, Su Tang, Xuelin Bian, Maloy K Parai, Inna V Krieger, Armando Flores, Pradeep K Jaiswal, Radha Bam, Jeremy L Wood, Zhe Shi, Laura J Stevens, Trevor Scobey, Meghan V Diefenbacher, Fernando R Moreira, Thomas J Baric, Arjun Acharya, Joonyoung Shin, Manish M Rathi, Karen C Wolff, Laura Riva, Malina A Bakowski, Case W McNamara, Nicholas J Catanzaro, Rachel L Graham, David C Schultz, Sara Cherry, Yoshihiro Kawaoka, Peter J Halfmann, Ralph S Baric, Mark R Denison, Timothy P Sheahan, James C Sacchettini","doi":"10.1016/j.celrep.2024.114929","DOIUrl":null,"url":null,"abstract":"<p><p>Safe, effective, and low-cost oral antiviral therapies are needed to treat those at high risk for developing severe COVID-19. To that end, we performed a high-throughput screen to identify non-peptidic, non-covalent inhibitors of the SARS-CoV-2 main protease (Mpro), an essential enzyme in viral replication. NZ-804 was developed from a screening hit through iterative rounds of structure-guided medicinal chemistry. NZ-804 potently inhibits SARS-CoV-2 Mpro (0.009 μM IC<sub>50</sub>) as well as SARS-CoV-2 replication in human lung cell lines (0.008 μM EC<sub>50</sub>) and primary human airway epithelial cell cultures. Antiviral activity is maintained against distantly related sarbecoviruses and endemic human CoV OC43. In SARS-CoV-2 mouse and hamster disease models, NZ-804 therapy given once or twice daily significantly diminished SARS-CoV-2 replication and pathogenesis. NZ-804 synthesis is low cost and uncomplicated, simplifying global production and access. These data support the exploration of NZ-804 as a therapy for COVID-19 and future emerging sarbecovirus infections.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"43 11","pages":"114929"},"PeriodicalIF":7.5000,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.celrep.2024.114929","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Safe, effective, and low-cost oral antiviral therapies are needed to treat those at high risk for developing severe COVID-19. To that end, we performed a high-throughput screen to identify non-peptidic, non-covalent inhibitors of the SARS-CoV-2 main protease (Mpro), an essential enzyme in viral replication. NZ-804 was developed from a screening hit through iterative rounds of structure-guided medicinal chemistry. NZ-804 potently inhibits SARS-CoV-2 Mpro (0.009 μM IC50) as well as SARS-CoV-2 replication in human lung cell lines (0.008 μM EC50) and primary human airway epithelial cell cultures. Antiviral activity is maintained against distantly related sarbecoviruses and endemic human CoV OC43. In SARS-CoV-2 mouse and hamster disease models, NZ-804 therapy given once or twice daily significantly diminished SARS-CoV-2 replication and pathogenesis. NZ-804 synthesis is low cost and uncomplicated, simplifying global production and access. These data support the exploration of NZ-804 as a therapy for COVID-19 and future emerging sarbecovirus infections.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
一种口服非共价非肽类 SARS-CoV-2 Mpro 抑制剂可改善体内病毒复制和致病机理。
我们需要安全、有效、低成本的口服抗病毒疗法来治疗那些极易罹患严重 COVID-19 的患者。为此,我们进行了一次高通量筛选,以确定 SARS-CoV-2 主蛋白酶 (Mpro) 的非肽、非共价抑制剂。NZ-804 是通过一轮又一轮的结构引导药物化学反应从筛选结果中开发出来的。NZ-804 能有效抑制 SARS-CoV-2 Mpro(0.009 μM IC50)以及 SARS-CoV-2 在人肺细胞系(0.008 μM EC50)和原发性人气道上皮细胞培养物中的复制。对远缘的沙巴病毒和地方性人类 CoV OC43 也有抗病毒活性。在 SARS-CoV-2 小鼠和仓鼠疾病模型中,每天服用 NZ-804 一次或两次可显著减少 SARS-CoV-2 的复制和致病机理。NZ-804 的合成成本低且不复杂,简化了全球生产和使用。这些数据支持将 NZ-804 作为治疗 COVID-19 和未来新出现的沙士病毒感染的一种疗法进行探索。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Cell reports
Cell reports CELL BIOLOGY-
CiteScore
13.80
自引率
1.10%
发文量
1305
审稿时长
77 days
期刊介绍: Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.
期刊最新文献
Combinatorial genetic engineering strategy for immune protection of stem cell-derived beta cells by chimeric antigen receptor regulatory T cells. O-GlcNAcylation modulates expression and abundance of N-glycosylation machinery in an inherited glycosylation disorder. ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Low-affinity ligands of the epidermal growth factor receptor are long-range signal transmitters in collective cell migration of epithelial cells. Leader cells promote immunosuppression to drive ovarian cancer progression in vivo.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1