https://doi.org/10.1016/j.apsb.2024.05.026
This new article publication from
Acta Pharmaceutica Sinica B, discusses the identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics.
There are only eight approved small molecule antiviral drugs for treating COVID-19. Among them, four are nucleotide analogues (remdesivir, JT001, molnupiravir, and azvudine), while the other four are protease inhibitors (nirmatrelvir, ensitrelvir, leritrelvir, and simnotrelvir-ritonavir). Antiviral resistance, unfavourable drug‒drug interaction, and toxicity have been reported in previous studies. Thus there is a dearth of new treatment options for SARS-CoV-2.
In this article, a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 activity. One compound, designated
172, demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of concern. Mechanistic studies validated by reverse genetics showed that compound
172 inhibits the 3-chymotrypsin-like protease (3CLpro) by binding to an allosteric site and reduces 3CLpro dimerization. A drug synergistic checkerboard assay demonstrated that compound
172 can achieve drug synergy with nirmatrelvir
in vitro.
In vivo studies confirmed the antiviral activity of compound
172 in both Golden Syrian Hamsters and K18 humanized ACE2 mice.
Overall, this study identified an alternative druggable site on the SARS-CoV-2 3CLpro, proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.
Keywords: SARS-CoV-2, High throughput screening, Broad-spectrum antiviral treatment, 3CLpro inhibitor, Allosteric-site inhibitor, Animal models, Chemical genetics, Reverse genetics
Graphical Abstract: available at
https://ars.els-cdn.com/content/image/1-s2.0-S2211383524002193-ga1_lrg.jpg
This study identifies a novel compound that blocks SARS-CoV-2 3CLpro dimerization, extending the enzyme's druggable pockets with an allosteric inhibitory mechanism.
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The Journal of the
Institute of Materia Medica, the Chinese Academy of Medical Sciences and the
Chinese Pharmaceutical Association.
For more information please visit
https://www.journals.elsevier.com/acta-pharmaceutica-sinica-b/
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CiteScore: 22.4
Impact Factor: 14.7 (Top 5 journal in the category of Pharmacology and pharmacy)
JIF without self-citation: 13.9
ISSN 2211-3835
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Chris Chun-Yiu Chan, Qian Guo, Jasper Fuk-Woo Chan, Kaiming Tang, Jian-Piao Cai, Kenn Ka-Heng Chik, Yixin Huang, Mei Dai, Bo Qin, Chon Phin Ong, Allen Wing-Ho Chu, Wan-Mui Chan, Jonathan Daniel Ip, Lei Wen, Jessica Oi-Ling Tsang, Tong-Yun Wang, Yubin Xie, Zhenzhi Qin, Jianli Cao, Zi-Wei Ye, Hin Chu, Kelvin Kai-Wang To, Xing-Yi Ge, Tao Ni, Dong-Yan Jin, Sheng Cui, Kwok-Yung Yuen, Shuofeng Yuan, Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics, Acta Pharmaceutica Sinica B, Volume 14, Issue 9, 2024, Pages 4028-4044, ISSN 2211-3835,
https://doi.org/10.1016/j.apsb.2024.05.026