Reversible Covalent Inhibitors?

[concordiascistudent]

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.

[BabcockHall]

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.