Despite the absence of druggable binding pockets and the difficulty to engage strong interactions in the active site in PL pro , our group rationally designed a first chemical series based on VIR-251 and GRL-0617 while four other novel chemical series of covalent inhibitors were discovered by virtual screening, all with micromolar range potencies in vitro. Preliminary SAR studies of the later four chemical series did not lead to inhibitors with potency low enough to warrant further investigation. In contrast, the design strategy of hybrid VIR-251 and GRL-0617 molecule was validated by biochemical assays which exhibited micromolar potency. Further optimization and testing of the hybrid molecule should be highly anticipated.