Nirmatrelvir has been approved by the US FDA (in combination with ritonavir) under the brand name of Paxlovid as a treatment for COVID-19. Recently, an analog of Nirmatrelvir in which the original nitrile warhead was replaced by a CF3-capped terminal alkyne was shown to be an effective irreversible inhibitor of SARS-Cov-2 M Pro . Capping the terminal alkyne with an appropriate group increased the potency by ~5-fold. The electrophilic nitrile warhead of Nirmatrelvir yields a more effective inhibitor of isolated M pro than the alkynecontaining analog independent of the scaffold; however, the increased potency of Nirmatrelvir over its alkyne-containing analog may be substantially reduced in live cells. Another example of recently discovered compounds with potent SARS-CoV-2 3CL protease inhibitory activity are peptidomimetics using an α-acyloxymethyl ketone as their warhead. The most potent of these compounds exhibited low cytotoxicity and good plasma and glutathione stability while possessing activity similar to that of the most potent inhibitors reported. The α-acyloxymethyl ketone warhead reacts irreversibly with the sulfhydryl group of Cys145 to form a covalent adduct. Excellent selectivity for SARS-CoV-2 3CL protease over other Cys proteases such as cathepsin B and S (CatB and CatS) indicates that acyloxymethyl ketones can be incorporated into selective protease inhibitors. The acyloxymethyl ketones also maintained good antiviral potency in multiple coronavirus strains (CoV-229E and CoV-OC43). 70