Potent and Selective Inhibitors of Human Sirtuin 5

Sirtuins
are protein deacylases that regulate metabolism and stress
responses and are implicated in aging-related diseases. Modulators
of the human sirtuins Sirt1–7 are sought as chemical tools
and potential therapeutics, e.g., for cancer. Selective and potent
inhibitors are available for Sirt2, but selective inhibitors for Sirt5
with Ki values in the low nanomolar range
are lacking. We synthesized and screened 3-arylthio­succinylated
and 3-benzylthio­succinylated peptide derivatives yielding Sirt5
inhibitors with low-nanomolar Ki values.
A biotinylated derivative with this scaffold represents an affinity
probe for human Sirt5 that is able to selectively extract this enzyme
out of complex biological samples like cell lysates. Crystal structures
of Sirt5/inhibitor complexes reveal that the compounds bind in an
unexpected manner to the active site of Sirt5.