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

页码：1095 / 1099

页数：5

共 50 条

[1] Drp1 recruitment by Mff, MiD51 and MiD49
Liu, R.
Chan, D. C.
MOLECULAR BIOLOGY OF THE CELL, 2015, 26
[2] Crystal structure and functional analysis of MiD49, a receptor for the mitochondrial fission protein Drp1
Loson, Oliver C.
Meng, Shuxia
Ngo, Huu
Liu, Raymond
Kaiser, Jens T.
Chan, David C.
PROTEIN SCIENCE, 2015, 24 (03) : 386 - 394
[3] Cooperative and independent roles of the Drp1 adaptors Mff, MiD49 and MiD51 in mitochondrial fission
Osellame, Laura D.
Singh, Abeer P.
Stroud, David A.
Palmer, Catherine S.
Stojanovski, Diana
Ramachandran, Rajesh
Ryan, Michael T.
JOURNAL OF CELL SCIENCE, 2016, 129 (11) : 2170 - 2181
[4] Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission
Loson, Oliver C.
Song, Zhiyin
Chen, Hsiuchen
Chan, David C.
MOLECULAR BIOLOGY OF THE CELL, 2013, 24 (05) : 659 - 667
[5] Fis1, Mff, MiD49 and MiD51 facilitate Drp1 recruitment for mitochondrial fission
Loson, Oliver Calvin
Chen, Hsiuchen
Chan, David C.
FASEB JOURNAL, 2013, 27
[6] Upregulation Of Mitochondrial Dynamin Related Protein-1 (drp1) Adapter Proteins Mid49 And Mid51 In Lung Cancer: A Novel Therapeutic Target
Chen, K. -H.
Dasgupta, A.
Mewburn, J. D.
Sykes, E.
Archer, S.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2017, 195
[7] The role of Drp1 adaptor proteins MiD49 and MiD51 in mitochondrial fission: implications for human disease
Atkins, Kathleen
Dasgupta, Asish
Chen, Kuang-Hueih
Mewburn, Jeff
Archer, Stephen L.
CLINICAL SCIENCE, 2016, 130 (21) : 1861 - 1874
[8] Discovery of Protein-Protein Interaction Inhibitors of Replication Protein A
Patrone, James D.
Kennedy, J. Phillip
Frank, Andreas O.
Feldkamp, Michael D.
Vangamudi, Bhavatarini
Pelz, Nicholas F.
Rossanese, Olivia W.
Waterson, Alex G.
Chazin, Walter J.
Fesik, Stephen W.
ACS MEDICINAL CHEMISTRY LETTERS, 2013, 4 (07): : 36 - 40
[9] Discovery of Novel Small-Molecule Inhibitors Disrupting the MTDH-SND1 Protein-Protein Interaction
Shen, Hao
Ding, Jiayu
Ji, Jiaying
Hu, Lingrong
Min, Wenjian
Hou, Yi
Wang, Dawei
Chen, Yuanyuan
Wang, Liping
Zhu, Yasheng
Wang, Xiao
Yang, Peng
JOURNAL OF MEDICINAL CHEMISTRY, 2025, 68 (02) : 1844 - 1862
[10] Protein-Protein Inhibitor Peptide of Drp1/Fis1 Interaction Protects the Heart Against Ischemia/Reperfusion Injury
Disatnik, Marie-Helene
Ferreira, Julio C.
Campos, Juliane Cruz
Gomes, Katia Sampaio
Dourado, Paulo M.
Qi, Xin
Mochly-Rosen, Daria
CIRCULATION, 2013, 128 (22)

← 1 2 3 4 5 →