Potent and Selective Inhibitors of Human Sirtuin 5
| Autor: | Corinna Popp, Clemens Steegborn, Wolfgang Sippl, Zayan Alhalabi, Marat Meleshin, Frank Bordusa, Martin Pannek, Sandra Liebscher, Diana Kalbas, Mike Schutkowski, Theresa Nowak |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine SIRT5 Antineoplastic Agents Peptide Crystallography X-Ray SIRT2 01 natural sciences Substrate Specificity 03 medical and health sciences Drug Discovery Humans Sirtuins chemistry.chemical_classification Molecular Structure biology 010405 organic chemistry Computational Biology Active site Metabolism Surface Plasmon Resonance Recombinant Proteins 0104 chemical sciences 030104 developmental biology Enzyme chemistry Biochemistry Biotinylation Sirtuin biology.protein Molecular Medicine Peptides |
| Zdroj: | Journal of Medicinal Chemistry. 61:2460-2471 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b01648 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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