Validation and invalidation of SARS-CoV-2 main protease inhibitors using the Flip-GFP and Protease-Glo luciferase assays
使用 Flip-GFP 和 Protease-Glo 荧光素酶检测验证和无效化 SARS-CoV-2 主要蛋白酶抑制剂
Flip-GFP 및 Protease-Glo 루시페라제 분석을 사용한 SARS-CoV-2 주요 프로테아제 억제제의 검증 및 무효화
Validación e invalidación de los principales inhibidores de la proteasa del SARS-CoV-2 mediante los ensayos de luciferasa Flip-GFP y Protease-Glo
Validation et invalidation des principaux inhibiteurs de la protéase du SRAS-CoV-2 à l'aide des tests Flip-GFP et Protease-Glo luciférase
Проверка и признание недействительными основных ингибиторов протеазы SARS-CoV-2 с использованием тестов люциферазы Flip-GFP и Protease-Glo
Chunlong Ma, Haozhou Tan, Juliana Choza, Yuying Wang, Jun Wang 王俊
Department of Pharmacology and Toxicology, College of Pharmacy, the University of Arizona, Tucson, AZ 85721, USA
Acta Pharmaceutica Sinica B, 1 November 2021

SARS-CoV-2 main protease (Mᵖʳᵒ) is one of the most extensively exploited drug targets for COVID-19. Structurally disparate compounds have been reported as Mᵖʳᵒ inhibitors, raising the question of their target specificity. To elucidate the target specificity and the cellular target engagement of the claimed Mᵖʳᵒ inhibitors, we systematically characterize their mechanism of action using the cell-free FRET assay, the thermal shift-binding assay, the cell lysate Protease-Glo luciferase assay, and the cell-based FlipGFP assay.

Collectively, our results have shown that majority of the Mᵖʳᵒ inhibitors identified from drug repurposing including ebselen, carmofur, disulfiram, and shikonin are promiscuous cysteine inhibitors that are not specific to Mᵖʳᵒ, while chloroquine, oxytetracycline, montelukast, candesartan, and dipyridamole do not inhibit Mᵖʳᵒ in any of the assays tested. Overall, our study highlights the need of stringent hit validation at the early stage of drug discovery.
Acta Pharmaceutica Sinica B_1
Acta Pharmaceutica Sinica B_2
Acta Pharmaceutica Sinica B_3
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