Tsuji Atsuhito, Masuya Takahiro, Arichi Norihito, Inuki Shinsuke, Murai Masatoshi, Miyoshi Hideto, Ohno Hiroaki
Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
ACS Med Chem Lett. 2023 Jan 24;14(2):211-216. doi: 10.1021/acsmedchemlett.2c00504. eCollection 2023 Feb 9.
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 () as an inhibitor targeting NADH-quinone oxidoreductase (complex I). Structural modifications of KPYC01112 () led to the discovery of the more potent inhibitors and possessing long alkyl chains (IC = 0.017 and 0.014 μM, respectively). A photoaffinity labeling experiment using a newly synthesized photoreactive bis-sulfonamide ([I]-) revealed that it binds to the 49-kDa, PSST, and ND1 subunits which make up the quinone-accessing cavity of complex I.
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的酶被认为是有前景的可成药靶点。通过用牛心亚线粒体颗粒筛选内部合成文库，我们鉴定出一种独特的对称双磺酰胺KPYC01112（）作为靶向NADH-醌氧化还原酶（复合体I）的抑制剂。KPYC01112（）的结构修饰导致发现了更有效的抑制剂和，它们具有长烷基链（IC分别为0.017和0.014μM）。使用新合成的光亲和标记双磺酰胺（[I]-）进行的光亲和标记实验表明，它与构成复合体I醌通道腔的49 kDa、PSST和ND1亚基结合。
