期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 11, 期 10, 页码 1886-1892出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00580
关键词
Sirtuins; histone deacetylases; enzyme inhibitors; mechanism-based inhibition; posttranslational modifications
资金
- University of Copenhagen
- Lundbeck Foundation (Running Cost grant) [R2892018-2074]
- Carlsberg Foundation [2013-01-033, CF15-0115]
- Novo Nordisk Foundation [NNF17OC0029464]
- European Research Council [ERC-CoG-725172-SIRFUNCT]
The sirtuin enzymes are potential drug targets for intervention in a series of diseases. Efforts to inhibit enzymes of this class with thioamide- and thiourea-containing, substrate-mimicking entities have produced a number of high-affinity binders. However, less attention has been dedicated to the investigation of the stability of these inhibitors under various conditions. Here, we provide evidence of an unprecedented degree of cleavage of short-chain epsilon-N-thioacyllysine modifications meant to target these sirtuins and further provide insights into the serum stability of compounds containing both thioamides and thioureas. Our study questions the utility short-chain thioamide-based inhibitors of sirtuins for drug development and points to monoalkylated thiourea-based chemotypes as being more stable in human serum.
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