Identification of Entry Inhibitors against Delta and Omicron Variants of SARS-CoV-2
Journal
International journal of molecular sciences
Journal Volume
23
Journal Issue
7
Pages
4050
Date Issued
2022-04-06
Author(s)
Lee, Richard Kuan-Lin
Li, Tian-Neng
Kuo, Chun-Hsien
Pan, Max Yu-Chen
Chiou, Yu-Ting
Liao, Kuan-Ju
Yang, Yi
Wu, Yi-Hsuan
Huang, Chen-Hao
Hsieh, Hsing-Pang
Wang, Lily Hui-Ching
Abstract
Entry inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed to control the outbreak of coronavirus disease 2019 (COVID-19). This study developed a robust and straightforward assay that detected the molecular interaction between the receptor-binding domain (RBD) of viral spike protein and the angiotensin-converting enzyme 2 (ACE2) receptor in just 10 min. A drug library of 1068 approved compounds was used to screen for SARS-CoV2 entry inhibition, and 9 active drugs were identified as specific pseudovirus entry inhibitors. A plaque reduction neutralization test using authentic SARS-CoV-2 virus in Vero E6 cells confirmed that 2 of these drugs (Etravirine and Dolutegravir) significantly inhibited the infection of SARS-CoV-2. With molecular docking, we showed that both Etravirine and Dolutegravir are preferentially bound to primary ACE2-interacting residues on the RBD domain, implying that these two drug blocks may prohibit the viral attachment of SARS-CoV-2. We compared the neutralizing activities of these entry inhibitors against different pseudoviruses carrying spike proteins from alpha, beta, gamma, and delta variants. Both Etravirine and Dolutegravir showed similar neutralizing activities against different variants, with EC50 values between 4.5 to 5.8 nM for Etravirine and 10.2 to 22.9 nM for Dolutegravir. These data implied that Etravirine and Dolutegravir may serve as general spike inhibitors against dominant viral variants of SARS-CoV-2.
Subjects
ACE2; COVID-19; SARS-CoV-2; entry inhibitor; receptor-binding domain; viral entry
Publisher
MDPI
Type
journal article