Potent and Specific Activators for Mitochondrial Sirtuins Sirt3 and Sirt5

Sirtuins are NAD+-dependent protein deacylases
involved
in metabolic regulation and aging-related diseases. Specific activators
for seven human Sirtuin isoforms would be important chemical tools
and potential therapeutic drugs. Activators have been described for
Sirt1 and act via a unique N-terminal domain of this isoform. For
most other Sirtuin isoforms, including mitochondrial Sirt3–5,
no potent and specific activators have yet been identified. We here
describe the identification and characterization of 1,4-dihydropyridine-based
compounds that either act as pan Sirtuin activators or specifically
stimulate Sirt3 or Sirt5. The activators bind to the Sirtuin catalytic
cores independent of NAD+ and acylated peptides and stimulate
turnover of peptide and protein substrates. The compounds also activate
Sirt3 or Sirt5 in cellular systems regulating, e.g., apoptosis and
electron transport chain. Our results provide a scaffold for potent
Sirtuin activation and derivatives specific for Sirt3 and Sirt5 as
an excellent basis for further drug development.