Peroxide derivatives as SARS-CoV-2 entry inhibitors

• Published in: Virus research 2024-02, Vol.340, p.199295-199295, Article 199295
• Main Authors: Zhang, Ding-Qi, Ma, Qin-Hai, Yang, Meng-Chu, Belyakova, Yulia Yu, Yang, Zi-Feng, Radulov, Peter S, Chen, Rui-Hong, Yang, Li-Jun, Wei, Jing-Yuan, Peng, Yu-Tong, Zheng, Wu-Yan, Yaremenko, Ivan A, Terent'ev, Alexander O, Coghi, Paolo, Wong, Vincent Kam Wai
• Format: Article
• Language: English
• Subjects: Bio-layer interferometry; RBD; SARS-CoV-2, peroxide, aminoperoxide derivatives, spike protein
• ISSN: 0168-1702; 1872-7492
• DOI: 10.1016/j.virusres.2023.199295

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Host cell invasion is mediated by the interaction of the viral spike protein (S) with human angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD). In this work, bio-layer interferometry (BLI) was used to screen a series of fifty-two peroxides, including aminoperoxides and bridged 1,2,4 - trioxolanes (ozonides), with the aim of identifying small molecules that interfere with the RBD-ACE2 interaction. We found that two compounds, compound 21 and 29, exhibit the activity to inhibit RBD-ACE2. They are further demonstrated to inhibit SARS-CoV-2 cell entry, as shown in pseudovirus assay and experiment with authentic SARS-CoV-2. A comprehensive in silico analysis was carried out to study the physicochemical and pharmacokinetic properties, revealing that both compounds have good physicochemical properties as well as good bioavailability. Our results highlight the potential of small molecules targeting RBD inhibitors as potential therapeutic drugs for COVID-19.