严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)
蛋白酶
2019年冠状病毒病(COVID-19)
对偶(语法数字)
2019-20冠状病毒爆发
病毒学
鉴定(生物学)
计算生物学
化学
组合化学
生物
医学
酶
生物化学
病理
哲学
传染病(医学专业)
疾病
爆发
植物
语言学
作者
Santo Previti,Roberta Ettari,Elsa Calcaterra,Michele Roggia,Benito Natale,Annabelle C. Weldert,Christin Müller,Florian Salisch,Anna Irto,Rosalia Maria Cigala,John Ziebuhr,Tanja Schirmeister,Sandro Cosconati,Maria Zappalà
标识
DOI:10.1021/acsmedchemlett.3c00562
摘要
In this structure–activity relationship (SAR) study, we report the development of dual inhibitors with antiviral properties targeting the SARS-CoV-2 main protease (Mpro) and human cathepsin L (hCatL). The novel molecules differ in the aliphatic amino acids at the P2 site and the fluorine position on the phenyl ring at the P3 site. The identified dual inhibitors showed Ki values within 1.61 and 10.72 μM against SARS-CoV-2 Mpro; meanwhile, Ki values ranging from 0.004 to 0.701 μM toward hCatL were observed. A great interdependency between the nature of the side chain at the P2 site and the position of the fluorine atom was found. Three dual-targeting inhibitors exhibited antiviral activity in the low micromolar range with CC50 values >100 μM. Docking simulations were executed to gain a deeper understanding of the SAR profile. The findings herein collected should be taken into consideration for the future development of dual SARS-CoV-2 Mpro/hCatL inhibitors.
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