Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.15.275891v1?rss=1 Authors: Westberg, M., Su, Y., Zou, X., Hurst, B., Tarbet, B., Lin, M. Abstract: The main protease, Mpro, of SARSCoV2 is a key protein in the coronavirus life cycle and a major drug target. Based on crystal structures of SARSCoV2 Mpro complexed with peptidomimetic inhibitors, we recognized a structural motif shared with approved inhibitors of hepatitis C virus protease. Initial tests showed that several HCV protease inhibitors could indeed also inhibit Mpro. Based on the identified molecular scaffolds we designed a new generation of ketoamide-based Mpro inhibitors with a preorganized backbone conformation. One of the designed inhibitors, ML1000, shows particularly high affinity towards Mpro and inhibits SARSCoV2 viral replication in human cells at sub-micromolar concentrations. Our findings identify ML1000 as a promising new scaffold for the development of anti-coronavirus drugs. Copy rights belong to original authors. Visit the link for more info