Discovery of Potent Allosteric DRP1 Inhibitors by Disrupting Protein-Protein Interaction with MiD49

被引：2
作者：
Furuya, Takeru [1 ,2 ]
Lin, Jean [1 ,3 ]
Afanaseva, Arina [1 ,4 ]
Molz, Lisa [1 ,5 ]
Lagu, Bharat [1 ]
Ma, Bin [1 ,6 ]
机构：
[1] Mitobridge Inc, Cambridge, MA 02138 USA
[2] Xontogeny, Boston, MA 02116 USA
[3] Mitobridge, Astellas, Cambridge, MA 02138 USA
[4] Astellas, Adv Informat & Analyt, Tsukuba, Ibaraki 3058585, Japan
[5] AvilarTherapeutics, Waltham, MA 02451 USA
[6] ArtBio Inc, Cambridge, MA 02142 USA
来源：
ACS MEDICINAL CHEMISTRY LETTERS | 2023年 / 14卷 / 08期
关键词：
DRP1; MiD49; Protein-proteininteraction; Allosteric; inhibitor; Mitochondria; MITOCHONDRIAL DIVISION DYNAMIN; SMALL-MOLECULE INHIBITORS; FISSION; FUSION;
D O I：
10.1021/acsmedchemlett.3c00223
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Mitochondrialdysfunction has been attributed to many disease indications, includingmetabolic, cardiovascular, neoplastic, and neurodegenerative diseases.Dynamin related protein 1 (DRP1) is crucial in regulating mitochondrialfission and maintaining mitochondrial homeostasis. MiD49 is a dynamicperipheral protein receptor on the surface of the mitochondrial membranethat recruits DRP1 protein to induce mitochondrial binary fission.By targeting the protein-protein interaction of DRP1/MiD49,we have discovered a novel and potent allosteric DRP1 inhibitor thatinhibits mitochondria fragmentation in vitro. X-raycocrystal structure revealed that it locked the closed DRP1 conformationby induced dimerization.
引用
收藏
页码：1095 / 1099
页数：5
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