Highly potent pancoronavirus fusion inhibitors also effectively inhibit UK, S.Africa COVID-19 variants

 Francesca Curreli, Shahad Ahmed, Sofia M. B. Victor, Aleksandra Drelich, Siva S. Panda, Andrea Altieri, Alexander Kurkin, Chien-Te Tseng, Christopher Hillyer,  

View ORCID ProfileAsim Debnath

doi: https://doi.org/10.1101/2021.09.03.458877

This article is a preprint and has not been certified by peer review [what does this mean?].

PDF: https://www.biorxiv.org/content/10.1101/2021.09.03.458877v1.full.pdf

Abstract

We report the discovery of a series of benzoic acid-based inhibitors that show highly potent pancoronavirus activity. Some compounds also show complete inhibition of CPE (IC100) at 1.25 μM against an authentic SARS-CoV-2 (US_WA-1/2020). Furthermore, the most active inhibitors also potently inhibited variants initially identified in the UK and South Africa. We confirmed that one of the potent inhibitors binds to the prefusion spike protein trimer of SARS-CoV-2 by SPR. Besides, we showed that they inhibit virus-mediated cell-cell fusion. The ADME data show druglike characteristics, and in vivo PK in rats demonstrated excellent half-life (t½) of 11.3 h, mean resident time (MRT) of 14.2 h, and orally bioavailable. Despite the presence of ene-rhodamine moiety, we conclusively demonstrated that these inhibitors target the viral spike protein and are not promiscuous or colloidal aggregators. We expect the lead inhibitors to pave the way for further development to preclinical and clinical candidates.

Competing Interest Statement

The authors have declared no competing interest.

https://www.biorxiv.org/content/10.1101/2021.09.03.458877v1