Reactivity of Nitroxyl-Derived Sulfinamides

Sulfinamide [RS­(O)­NH2] formation is known
to occur upon
exposure of cysteine residues to nitroxyl (HNO), which has received
recent attention as a potential heart failure therapeutic. Because
this modification can alter protein structure and function, we have
examined the reactivity of sulfinamides in several systems, including
a small organic molecule, peptides, and a protein. Although it has
generally been assumed that this thiol to sulfinamide modification
is irreversible, we show that sulfinamides can be reduced back to
the free thiol in the presence of excess thiol at physiological pH
and temperature. We have examined this sulfinamide reduction both
in peptides, where a cyclic intermediate analogous to that proposed
for asparagine deamidation reactions potentially can contribute, and
in a small organic molecule, where the mechanism is restricted to
a direct thiolysis. These studies suggest that the contribution from
the cyclic intermediate becomes more important in environments with
lower dielectric constants. In addition, although sulfinic acid [RS­(O)­OH]
formation is observed upon prolonged incubations in water, reduction
of sulfinamides is found to dominate in the presence of thiols. Finally,
studies with the cysteine protease, papain, suggest that the reduction
of sulfinamide to the free thiol is viable in a protein environment.