Granzyme Inhibitors

Chemical inhibitors of granzyme B function by impeding the enzyme's ability to induce apoptosis in target cells. Serpin B9, for instance, serves as a specific inhibitor by forming a complex with granzyme B, effectively obstructing its enzymatic activity. This interaction prevents granzyme B from cleaving its substrates, thereby inhibiting the apoptotic signal. Similarly, Z-AAD-CMK targets the enzyme directly, binding irreversibly to its active site and preventing substrate access. This binding renders granzyme B inactive, as it can no longer engage with the proteins it typically cleaves during the execution of apoptosis. Another inhibitor, UCF-101, operates through a similar mechanism by selectively binding to the active site of granzyme B, which inhibits the cleavage of vital apoptotic substrates. The inhibition of granzyme B is also achieved through the action of various broad-spectrum inhibitors that affect serine proteases in general. Gabexate mesilate and Nafamostat mesilate both act by forming a stable complex at the active site of the enzyme, which averts the activation of proteins that are crucial for the apoptosis pathway. AEBSF functions by covalently modifying the active serine residue within granzyme B, leading to a loss of enzymatic activity. Sunflower trypsin inhibitor-1 employs a strategy where it binds to the active site of serine proteases, including granzyme B, preventing them from engaging with and cleaving their intended substrates. Although not as specific as some of the other inhibitors, compounds like Isophosphoramide mustard and Belactosin C indirectly influence granzyme B activity. Isophosphoramide mustard by forming DNA crosslinks that can affect the cells producing granzyme B, and Belactosin C by inhibiting the proteasome, which is involved in the degradation and processing of proteins, including granzymes. Sivelestat, while primarily targeting neutrophil elastase, can have downstream effects that modulate immune responses involving granzyme secretion. E-64, although primarily targeting cysteine proteases, can also inhibit granzyme K, another member of the granzyme family, by binding to its active site cysteine residue.