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Discovery of highly potent pancoronavirus fusion inhibitors that also effectively inhibit COVID-19 variants from the UK (Alpha), South Africa (Beta), and India (Delta)

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

Posted 03 Sep 2021
bioRxiv DOI: 10.1101/2021.09.03.458877

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 M 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 drug-like characteristics, and in vivo PK in rats demonstrated excellent half-life (t1/2) 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/458877v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@ada063org.highwire.dtl.DTLVardef@fcc4f4org.highwire.dtl.DTLVardef@e69ac3org.highwire.dtl.DTLVardef@1ba880e_HPS_FORMAT_FIGEXP M_FIG Table of Contents Graphics C_FIG

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