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07:35
Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess
Published on: June 1, 2022
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Second-Generation Inhibitors of the Mitochondrial Permeability Transition Pore with Improved Plasma Stability
Justina Šileikytė1, Jordan Devereaux2, Jelle de Jong3
1Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
Chemmedchem
|August 20, 2019
Summary
New triazole compounds effectively inhibit the mitochondrial permeability transition pore (mtPTP), offering improved stability for potential therapeutic applications in diseases linked to cell death.
Area of Science:
- Biochemistry
- Pharmacology
- Cell Biology
Background:
- Mitochondrial permeability transition pore (mtPTP) opening, triggered by matrix Ca2+ and oxidative stress, contributes to cell death in various diseases.
- mtPTP inhibitors are pursued as therapeutics, but early candidates like isoxazoles have poor in vivo stability.
Purpose of the Study:
- To develop novel mtPTP inhibitors with enhanced plasma stability.
- To evaluate the efficacy of new triazole-based analogues in a disease model.
Main Methods:
- High throughput screening identified isoxazole compounds as mtPTP inhibitors.
- Copper-catalyzed click chemistry was used to synthesize triazole analogues.
- Efficacy was tested in a zebrafish model of muscular dystrophy.
Main Results:
- Triazole analogues demonstrated improved plasma stability compared to isoxazoles.
- Compound TR001 showed efficacy in a zebrafish model of mtPTP-related muscular dystrophy.
- The isoxazole analogue had minimal effect in the same model.
Conclusions:
- Replacing the isoxazole core with a triazole significantly enhances compound stability.
- Triazole-based mtPTP inhibitors represent a promising therapeutic strategy for diseases involving mtPTP dysfunction.
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