Identification of SARS-CoV-2 Mpro inhibitors containing P1’ 4-fluorobenzothiazole moiety highly active against SARS-CoV-2

Author:

Higashi-Kuwata NobuyoORCID,Tsuji KoheiORCID,Hayashi HironoriORCID,Bulut HaydarORCID,Kiso Maki,Imai Masaki,Ogata-Aoki HiromiORCID,Ishii TakahiroORCID,Kobayakawa TakuyaORCID,Nakano Kenta,Takamune NobutokiORCID,Kishimoto NaokiORCID,Hattori Shin-ichiroORCID,Das DebanandaORCID,Uemura Yukari,Shimizu YosukeORCID,Aoki ManabuORCID,Hasegawa KazuyaORCID,Suzuki SatoshiORCID,Nishiyama AkieORCID,Saruwatari JunjiORCID,Shimizu YukikoORCID,Sukenaga Yoshikazu,Takamatsu YukiORCID,Tsuchiya KiyotoORCID,Maeda Kenji,Yoshimura Kazuhisa,Iida ShunORCID,Ozono Seiya,Suzuki TadakiORCID,Okamura TadashiORCID,Misumi ShogoORCID,Kawaoka YoshihiroORCID,Tamamura HirokazuORCID,Mitsuya HiroakiORCID

Abstract

Abstract COVID-19 caused by SARS-CoV-2 has continually been serious threat to public health worldwide. While a few anti-SARS-CoV-2 therapeutics are currently available, their antiviral potency is not sufficient. Here, we identify two orally available 4-fluoro-benzothiazole-containing small molecules, TKB245 and TKB248, which specifically inhibit the enzymatic activity of main protease (Mpro) of SARS-CoV-2 and significantly more potently block the infectivity and replication of various SARS-CoV-2 strains than nirmatrelvir, molnupiravir, and ensitrelvir in cell-based assays employing various target cells. Both compounds also block the replication of Delta and Omicron variants in human-ACE2-knocked-in mice. Native mass spectrometric analysis reveals that both compounds bind to dimer Mpro, apparently promoting Mpro dimerization. X-ray crystallographic analysis shows that both compounds bind to Mpro’s active-site cavity, forming a covalent bond with the catalytic amino acid Cys-145 with the 4-fluorine of the benzothiazole moiety pointed to solvent. The data suggest that TKB245 and TKB248 might serve as potential therapeutics for COVID-19 and shed light upon further optimization to develop more potent and safer anti-SARS-CoV-2 therapeutics.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

Cited by 18 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3