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PLpro inhibitors are currently under development and many emerging PLpro inhibitors are derived from GRL0617, a repurposed SARS-CoV PLpro inhibitor with moderate activity against SARS-CoV-2. Two leading derivatives, PF-07957472 and Jun12682, demonstrate low nanomolar activity and display activity in mice. WEHI-P8 is structurally distinct but binds to a similar pocket adjacent to the active site as GRL0617-like compounds. Using deep mutational scanning, we assessed the potential for PLpro to develop resistance to PF-07957472, Jun12682, and WEHI-P8. PF-07957472 and Jun12682 exhibited largely overlapping escape mutations due to their shared scaffold and binding modes, whereas WEHI-P8 resistance mutations were distinct. 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