Calpain II Inhibitors

Chemical inhibitors of Calpain Inhibitor II operate through various mechanisms to impede the protein's function. ALLN, for instance, targets Calpain Inhibitor II with a covalent modification of the enzyme's active site cysteine residue. This modification obstructs the binding and processing of substrates, effectively shutting down the protein's proteolytic activity. Similarly, E-64 employs an irreversible binding to the same cysteine residue within the catalytic domain, which blocks substrate access and halts enzymatic function. PD150606, on the other hand, binds to the calcium-binding sites essential for Calpain Inhibitor II activation. By occupying these sites, PD150606 ensures that the conformational change required for enzyme activation does not occur, thus inhibiting its activity.

Further down the list of inhibitors, MDL28170 and Calpeptin directly interact with the active site of Calpain Inhibitor II. MDL28170 prevents the hydrolysis of natural substrates by binding to the catalytic domain, while Calpeptin blocks the active site, disrupting the enzyme's interaction with its substrates. AK295 inhibits by binding to the calcium-binding domain of Calpain Inhibitor II, resulting in a reduction of the enzyme's proteolytic activity. Z-Leu-Leu-Nle-CHO mimics natural substrates to irreversibly bind to and block the active site, thus preventing the enzyme from performing its function. SJA6017 and BDA-410 both act by binding to the active site, with SJA6017 preventing substrate entry and BDA-410 allosterically modifying the enzyme to reduce its activity. Gabexate mesilate, though less specific, also binds to the active site and inhibits substrate interaction. Each of these chemicals ensures the inhibition of Calpain Inhibitor II by preventing either substrate binding, substrate cleavage, or the necessary conformational changes for enzymatic activity.