Potent and Selective Inhibitors of Human Sirtuin 5

Journal of Medicinal Chemistry
Diana KalbasMike Schutkowski

Abstract

Sirtuins are protein deacylases that regulate metabolism and stress responses and are implicated in aging-related diseases. Modulators of the human sirtuins Sirt1-7 are sought as chemical tools and potential therapeutics, e.g., for cancer. Selective and potent inhibitors are available for Sirt2, but selective inhibitors for Sirt5 with Ki values in the low nanomolar range are lacking. We synthesized and screened 3-arylthiosuccinylated and 3-benzylthiosuccinylated peptide derivatives yielding Sirt5 inhibitors with low-nanomolar Ki values. A biotinylated derivative with this scaffold represents an affinity probe for human Sirt5 that is able to selectively extract this enzyme out of complex biological samples like cell lysates. Crystal structures of Sirt5/inhibitor complexes reveal that the compounds bind in an unexpected manner to the active site of Sirt5.

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Citations

Apr 12, 2018·Critical Reviews in Biochemistry and Molecular Biology·Surinder Kumar, David B Lombard
Oct 3, 2019·Journal of the American Society of Nephrology : JASN·Takuto ChibaSunder Sims-Lucas
Apr 2, 2020·Expert Opinion on Therapeutic Patents·Nicola MautoneDante Rotili
Jun 5, 2019·Medicinal Chemistry·Yanhong Jiang, Weiping Zheng
Dec 6, 2018·Frontiers in Immunology·Tytti HeinonenThierry Roger
Aug 8, 2020·Clinical Epigenetics·Ranim El Baba, Georges Herbein
Jan 8, 2021·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Kevin PeasleySunder Sims-Lucas
Aug 31, 2021·European Journal of Medicinal Chemistry·Fan YangLingling Yang

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