Yunlong Shi, Ari Zeida, Caitlin E Edwards, Michael L Mallory, Santiago Sastre, Matías R Machado, Raymond J Pickles, Ling Fu, Keke Liu, Jing Yang, Ralph S Baric, Richard C Boucher, Rafael Radi, Kate S Carroll
The development of small-molecules targeting different components of SARS-CoV-2 is a key strategy to complement antibody-based treatments and vaccination campaigns in managing the COVID-19 pandemic. Here, we show that two thiol-based chemical probes that act as reducing agents, P2119 and P2165, inhibit infection by human coronaviruses, including SARS-CoV-2, and decrease the binding of spike glycoprotein to its receptor, the angiotensin-converting enzyme 2 (ACE2). Proteomics and reactive cysteine profiling link the antiviral activity to the reduction of key disulfides, specifically by disruption of the Cys379-Cys432 and Cys391-Cys525 pairs distal to the receptor binding motif in the receptor binding domain (RBD) of the spike glycoprotein...
February 8, 2022: Proceedings of the National Academy of Sciences of the United States of America