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Potent and Selective Inhibitors of Human Sirtuin 5
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-01 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01648 Diana Kalbas 1 , Sandra Liebscher 2 , Theresa Nowak 3 , Marat Meleshin 1 , Martin Pannek 4 , Corinna Popp 1 , Zayan Alhalabi 3 , Frank Bordusa 2 , Wolfgang Sippl 3 , Clemens Steegborn 4 , Mike Schutkowski 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-01 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01648 Diana Kalbas 1 , Sandra Liebscher 2 , Theresa Nowak 3 , Marat Meleshin 1 , Martin Pannek 4 , Corinna Popp 1 , Zayan Alhalabi 3 , Frank Bordusa 2 , Wolfgang Sippl 3 , Clemens Steegborn 4 , Mike Schutkowski 1
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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.
中文翻译：
人类Sirtuin 5的有力和选择性抑制剂。
Sirtuins是调节代谢和应激反应的蛋白质脱酰基酶，与衰老相关的疾病有关。人们正在寻找人类sirtuins Sirt1-7的调节剂，作为化学工具和潜在疗法，例如用于癌症。选择性的和有效的抑制剂可用于Sirt2的，但对于Sirt5的选择性抑制剂与ķ我在低纳摩尔范围内的值所缺乏的。我们合成并筛选了可产生具有低纳摩尔K i的Sirt5抑制剂的3-芳基硫代琥珀酰化和3-苄基硫代琥珀酰化的肽衍生物。价值观。具有该支架的生物素化衍生物代表人Sirt5的亲和探针，该探针能够从复杂的生物样品（如细胞裂解物中）选择性地提取这种酶。Sirt5 /抑制剂复合物的晶体结构表明，该化合物以意想不到的方式与Sirt5的活性位点结合。
更新日期：2018-03-01
中文翻译：
人类Sirtuin 5的有力和选择性抑制剂。
Sirtuins是调节代谢和应激反应的蛋白质脱酰基酶，与衰老相关的疾病有关。人们正在寻找人类sirtuins Sirt1-7的调节剂，作为化学工具和潜在疗法，例如用于癌症。选择性的和有效的抑制剂可用于Sirt2的，但对于Sirt5的选择性抑制剂与ķ我在低纳摩尔范围内的值所缺乏的。我们合成并筛选了可产生具有低纳摩尔K i的Sirt5抑制剂的3-芳基硫代琥珀酰化和3-苄基硫代琥珀酰化的肽衍生物。价值观。具有该支架的生物素化衍生物代表人Sirt5的亲和探针，该探针能够从复杂的生物样品（如细胞裂解物中）选择性地提取这种酶。Sirt5 /抑制剂复合物的晶体结构表明，该化合物以意想不到的方式与Sirt5的活性位点结合。
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