Structure-based discovery of PL pro inhibitors. Shortly after the start of the COVID19 outbreak, highquality crystal structures were published, creating an opportunity for structure-based drug design. Taking advantage of our expertise in covalent inhibition, computational drug discovery, and virtual screening of covalent inhibitors, we sought to design, synthesize and evaluate PL pro inhibitors using rational design and large library virtual screening. We report herein our efforts over the past two years in the design and synthesis of PL pro inhibitors and in the discovery through virtual screening of novel chemical series for this enzyme.