Hi,

 

My group is researching nirmatrelvir's binding to the SARS-CoV-2 main protease and all the literature says it is a "reversible covalent inhibitor." As I was taught it, covalent inhibition is permanent, so how is the nirmatrelvir reaction reversible? I know the nirmatrelvir nitrile warhead bonds with the Cys145 of Mpro, but that's about it.

Many covalent inhibitors are irreversible, but not all of them are.  If each step to form a covalent bond is reversible, then the whole process is reversible.  A good example is peptide aldehyde or trifluromethylketone binding to the nucleophile in a cysteine or serine proteases.  Reversible, covalent inhibitors seem to be catching on, so it's a good topic.