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

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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.

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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。

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来源期刊

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.