Potent sirtuin inhibition bestowed by l-2-amino-7-carboxamidoheptanoic acid (l-ACAH), a Nε-acetyl-lysine analog

Abstract

Inhibitors of sirtuin-catalyzed NAD⁺-dependent proteinlysine deacetylation reaction possess great value for a fuller exploration of sirtuin biology/pharmacology and as potential therapeutic agents for metabolic and age-related diseases and cancer. In the current study, we discovered that L-2-amino-7-carboxamidoheptanoic acid (L-ACAH), a N^ε-acetyl-lysine analog, could confer potent SIRT1 inhibition in both the peptidic and the peptidomimetic inhibitors. This inhibition was demonstrated to be mechanism-based since the in vitro studies with the peptidic inhibitor revealed that (i) the inhibitor was competitive versus the acetyl-lysine substrate, (ii) the inhibitor was of the slow, tight-binding type, and (iii) the inhibitor was able to be converted to at least one longer-lived catalytic intermediate and perhaps all the way to the product (similar to 2′-O-acetyl-ADP-ribose) as well. The in vivo characterization of the peptidomimetic inhibitor revealed its capability of inhibiting the SIRT1 inside the human colon cancer cell line HCT116. This peptidomimetic compound was also shown to be an in vitroinhibitor against SIRT2 and SIRT3 with comparable potency to that against SIRT1. These results point to the potential of developing further potent cell permeable L-ACAH-based inhibitors for sirtuins.