Cyclic tripeptide-based potent human SIRT7 inhibitors.

Graphical abstract Highlights • Two first examples of potent (low μM) inhibitors against the tRNA-activated human SIRT7 deacetylase activity were found. • The two inhibitors are cyclic tripeptides each harboring a catalytic mechanism-based sirtuin inhibitory warhead. • The two inhibitors also exhibited potent (low μM) inhibition against the deacylase activities of human SIRT1/2/3/6. • Our finding could facilitate the future development of more potent and selective human SIRT7 inhibitors. Abstract In the current study, two cyclic tripeptides respectively harboring a thiourea-type and a carboxamide-type of catalytic mechanism-based sirtuin inhibitory warheads as the central residue were found to behave as potent (low μM level) inhibitors against the tRNA-activated human SIRT7 deacetylase activity. Despite exhibiting a potent pan-inhibition against the deacylase activities of the five tested human sirtuins (i.e. SIRT1/2/3/6/7), these two compounds represent the first examples of potent SIRT7 inhibitors ever identified thus far, and their identification could facilitate the future development of more potent and selective SIRT7 inhibitors. [ABSTRACT FROM AUTHOR]