Rhenium(V) Complexes as Cysteine-Targeting Coordinate Covalent Warheads

Interest in covalent enzyme inhibitors as therapeutic
agents has
seen a recent resurgence. Covalent enzyme inhibitors typically possess
an organic functional group that reacts with a key feature of the
target enzyme, often a nucleophilic cysteine residue. Herein, the
application of small, modular ReV complexes as inorganic
cysteine-targeting warheads is described. These metal complexes were
found to react with cysteine residues rapidly and selectively. To
demonstrate the utility of these ReV complexes, their reactivity
with SARS-CoV-2-associated cysteine proteases is presented, including
the SARS-CoV-2 main protease and papain-like protease and human enzymes
cathepsin B and L. As all of these proteins are cysteine proteases,
these enzymes were found to be inhibited by the ReV complexes
through the formation of adducts. These findings suggest that these
ReV complexes could be used as a new class of warheads
for targeting surface accessible cysteine residues in disease-relevant
target proteins.