 The SARS-CoV-2 propane-like proteins, PL-PRO, is of interest as an antiviral drug target. Here, the authors synthesize and characterize naphthalene-based inhibitors for PL-PRO and present the crystal structures of PL-PRO in its apo-state and with the bound inhibitors, which is of interest for further structure-based drug design efforts. This article was authored by Jersey Ossipiac, Sara Anazizzi, Steve Dworkin, and others.