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 .
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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
Acta Pharmaceutica Sinica B
6-Sep-2024