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Potent and Selective Inhibitors of Human Sirtuin 5

Title data

Kalbas, Diana ; Liebscher, Sandra ; Nowak, Theresa ; Meleshin, Marat ; Pannek, Martin ; Popp, Corinna ; Alhalabi, Zayan ; Bordusa, Frank ; Sippl, Wolfgang ; Steegborn, Clemens ; Schutkowski, Mike:
Potent and Selective Inhibitors of Human Sirtuin 5.
In: Journal of Medicinal Chemistry. Vol. 61 (12 March 2018) Issue 6 . - pp. 2460-2471.
ISSN 1520-4804
DOI: https://doi.org/10.1021/acs.jmedchem.7b01648

Abstract in another language

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 Kvalues in the low nanomolar range are lacking. We synthesized and screened 3-arylthiosuccinylated and 3-benzylthiosuccinylated peptide derivatives yielding Sirt5 inhibitors with low-nanomolar Kvalues. 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.

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
Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry
Result of work at the UBT: Yes
DDC Subjects: 500 Science > 540 Chemistry
Date Deposited: 22 Mar 2018 06:56
Last Modified: 22 Mar 2018 06:57
URI: https://eref.uni-bayreuth.de/id/eprint/43080