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Potent and Specific Activators for Mitochondrial Sirtuins Sirt3 and Sirt5

Title data

Suenkel, Benjamin ; Valente, Sergio ; Zwergel, Clemens ; Weiss, Sandra ; Di Bello, Elisabetta ; Fioravanti, Rossella ; Aventaggiato, Michele ; Amorim, João A. ; Garg, Neha ; Kumar, Surinder ; Lombard, David B. ; Hu, Tuo ; Singh, Pankaj K. ; Tafani, Marco ; Palmeira, Carlos M. ; Sinclair, David ; Mai, Antonello ; Steegborn, Clemens:
Potent and Specific Activators for Mitochondrial Sirtuins Sirt3 and Sirt5.
In: Journal of Medicinal Chemistry. Vol. 65 (2022) Issue 20 . - pp. 14015-14031.
ISSN 1520-4804
DOI: https://doi.org/10.1021/acs.jmedchem.2c01215

Abstract in another language

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.

Further data

Item Type: Article in a journal
Refereed: Yes
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn
Result of work at the UBT: Yes
DDC Subjects: 500 Science > 540 Chemistry
500 Science > 570 Life sciences, biology
Date Deposited: 10 Nov 2022 08:32
Last Modified: 10 Nov 2022 08:32
URI: https://eref.uni-bayreuth.de/id/eprint/72730