From noncovalent fragment to (non)covalent leads against PLPro

The most successful drug against COVID-19, nirmatrelvir, targets the main protease of SARS-CoV-2. As we discussed just last year, this protein has received considerable attention. But the genome for SARS-CoV-2 also encodes a second cysteine protease, papain-like protease, or PLPro. Despite this enzyme being essential for viral replication, the only previously disclosed chemical series targeting it dates from 2008 efforts against the original SARS. Two new papers in J. Med. Chem. from Stephen Fesik...