Discovery of Potent Allosteric DRP1 Inhibitors by Disrupting Protein-Protein Interaction with MiD49
Takeru Furuya1, Jean Lin1, Arina Afanaseva1
1Mitobridge, Inc., an Astellas Company, Cambridge, Massachusetts 02138, United States.
Abstract:
Mitochondrial dysfunction has been attributed to many disease indications, including metabolic, cardiovascular, neoplastic, and neurodegenerative diseases. Dynamin related protein 1 (DRP1) is crucial in regulating mitochondrial fission and maintaining mitochondrial homeostasis. MiD49 is a dynamic peripheral protein receptor on the surface of the mitochondrial membrane that 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 that inhibits mitochondria fragmentation in vitro. X-ray cocrystal structure revealed that it locked the closed DRP1 conformation by induced dimerization.
Insights
Researchers discovered a novel drug that inhibits mitochondrial fragmentation by targeting the DRP1/MiD49 interaction. This finding offers a new therapeutic strategy for diseases linked to mitochondrial dysfunction.
Area of Science:
- Cell Biology
- Biochemistry
- Pharmacology
Background:
- Mitochondrial dysfunction is implicated in various diseases, including metabolic, cardiovascular, neoplastic, and neurodegenerative disorders.
- Dynamin-related protein 1 (DRP1) plays a critical role in mitochondrial fission and homeostasis.
- MiD49 acts as a mitochondrial receptor, recruiting DRP1 to facilitate mitochondrial division.
Purpose of the Study:
- To identify and characterize a novel inhibitor targeting the DRP1/MiD49 protein-protein interaction.
- To investigate the potential of inhibiting mitochondrial fragmentation for therapeutic purposes.
Main Methods:
- Development of a novel allosteric DRP1 inhibitor.
- In vitro assays to assess the inhibitor's effect on mitochondria fragmentation.
- X-ray crystallography to determine the inhibitor's mechanism of action.
Main Results:
- A potent allosteric DRP1 inhibitor was discovered that effectively inhibits mitochondria fragmentation in vitro.
- X-ray cocrystal structure revealed the inhibitor locks DRP1 in a closed conformation via induced dimerization.
- The inhibitor targets the DRP1/MiD49 interaction, a key regulator of mitochondrial fission.
Conclusions:
- Targeting the DRP1/MiD49 interaction with novel allosteric inhibitors presents a promising therapeutic approach.
- Inhibition of mitochondrial fragmentation may offer a new strategy for treating diseases associated with mitochondrial dysfunction.
