Discovery of new human Sirtuin 5 inhibitors by mimicking glutaryl-lysine substrates
| Autor: | Guo-Bo Li, Hua-Li Wang, Fan Yang, Luohe Mou, Shan Qian, Ji Deng, Yu-Hang Yan, Rong Li, Yang Lingling, Qing-Qing Dai, Zhouyu Wang, Huilin Su |
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| Rok vydání: | 2021 |
| Předmět: |
SIRT5
High selectivity Lysine Nicotinamide adenine dinucleotide Cofactor Substrate Specificity chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Humans Sirtuins Epigenetics Enzyme Inhibitors Pharmacology biology Dose-Response Relationship Drug Molecular Structure Organic Chemistry Thiourea General Medicine Metabolic pathway Biochemistry chemistry Sirtuin biology.protein Propionates |
| Zdroj: | European journal of medicinal chemistry. 225 |
| ISSN: | 1768-3254 |
| Popis: | Human sirtuin 5 (SIRT5) plays pivotal roles in metabolic pathways and other biological processes, and is involved in several human diseases including cancer. Development of new potent and selective SIRT5 inhibitors is currently desirable to provide potential therapeutics for related diseases. Herein, we report a series of new 3-thioureidopropanoic acid derivatives, which were designed to mimic the binding features of SIRT5 glutaryl-lysine substrates. Structure-activity relationship studies revealed several compounds with low micromolar inhibitory activities to SIRT5. Computational and biochemical studies indicated that these compounds exhibited competitive SIRT5 inhibition with respect to the glutaryl-lysine substrate rather than nicotinamide adenine dinucleotide cofactor. Moreover, they showed high selectivity for SIRT5 over SIRT1-3 and 6 and could stabilize SIRT5 proteins as revealed by thermal shift analyses. This work provides an effective substrate-mimicking strategy for future inhibitor design, and offers new inhibitors to investigate their therapeutic potentials in SIRT5-associated disease models. |
| Databáze: | OpenAIRE |
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