Discovery of potent, proteolytically stable, and cell permeable human sirtuin peptidomimetic inhibitors containing Nε-thioacetyl-lysine

Inhibitors of sirtuin-catalyzed NAD+-dependent protein lysine deacetylation reaction possess great value for facilitating deciphering the biology of sirtuins and as potential therapeutic agents for metabolic and age-related diseases and cancer. Built upon our previously discovered potent Ne-thioacetyl-lysine (ThAcK)-containing 18-amino acid peptidic human sirtuin inhibitor 1, we performed a structure–activity-relationship (SAR) study with the goal of transforming this potent peptidic inhibitor to potent yet proteolytically stable, cell permeable, and low molecular weight ThAcK-containing peptidomimetic inhibitors. Specifically, in this SAR study, we have identified two such peptidomimetic inhibitors (8 and 9) that exhibited potent in vitro and in vivo human sirtuin inhibition and whose molecular weights are in the 500 Da range.