Discovery of Bis-sulfonamides as Novel Inhibitors of Mitochondrial NADH-Quinone Oxidoreductase (Complex I)
Discovery of Bis-sulfonamides as Novel Inhibitors of Mitochondrial NADH-Quinone Oxidoreductase (Complex I)
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发现双磺酰胺作为线粒体 NADH-醌氧化还原酶（复合物 I）的新型抑制剂
DOI：
10.1021/acsmedchemlett.2c00504
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发表时间：
2023
影响因子：
4.2
通讯作者：
Ohno Hiroaki
中科院分区：
文献类型：
--
作者：
Tsuji Atsuhito;Masuya Takahiro;Arichi Norihito;Inuki Shinsuke;Murai Masatoshi;Miyoshi Hideto;Ohno Hiroaki
线粒体氧化磷酸化（OXPHOS）是产生ATP的重要细胞代谢过程。参与OXPHOS的酶被认为是有前途的药物靶标。通过用牛心脏亚线粒体颗粒筛选内部合成文库，我们鉴定了一种独特的对称双磺酰胺KPYC 01112（1）作为靶向NADH-醌氧化还原酶（复合物I）的抑制剂。KPYC 01112（1）的结构修饰导致发现了具有长烷基链的更有效的底物32和35（IC 50分别为0.017和0.014 μM）。使用新合成的光反应性双磺酰胺（[125 I]-43）进行的光亲和标记实验显示，其与组成复合物I的醌进入腔的49-kDa、PSST和ND 1亚基结合。
Mitochondrial oxidative phosphorylation (OXPHOS) is an essential cellular metabolic process that generates ATP. The enzymes involved in OXPHOS are considered to be promising druggable targets. Through screening of an in-house synthetic library with bovine heart submitochondrial particles, we identified a unique symmetric bis-sulfonamide, KPYC01112 (1) as an inhibitor targeting NADH-quinone oxidoreductase (complex I). Structural modifications of KPYC01112 (1) led to the discovery of the more potent inhibitors32and35possessing long alkyl chains (IC50= 0.017 and 0.014 μM, respectively). A photoaffinity labeling experiment using a newly synthesized photoreactive bis-sulfonamide ([125I]-43) revealed that it binds to the 49-kDa, PSST, and ND1 subunits which make up the quinone-accessing cavity of complex I.