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The novel cyclophilin inhibitor C105SR reduces hepatic ischaemia-reperfusion injury via mitoprotection
Amel Kheyar1, Nazim Ahnou1, Abdelhakim Ahmed-Belkacem1
1Équipe "Virus, Hépatologie, Cancer", INSERM U955, IMRB, Université Paris-Est, Créteil, France.
Background & Aims:
Mitochondrial permeability transition pore (mPTP) opening is critical for mediating cell death during hepatic ischaemia-reperfusion injury (IRI). Blocking mPTP opening by inhibiting cyclophilin D (CypD) is a promising pharmacological approach for the treatment of IRI. Here, we show that diastereoisomers of a new class of small-molecule cyclophilin inhibitors (SMCypIs) have properties that make them attractive candidates for the development of therapeutic agents against liver IRI.
Methods:
Derivatives of the parent SMCypI were synthesised and evaluated for their ability to inhibit CypD peptidyl-prolyl cis-trans isomerase (PPIase) activity and for their mitoprotective properties, evaluated by measuring mitochondrial swelling and calcium retention capacity in liver mitochondria. The ability of the selected compounds to inhibit mPTP opening was evaluated in cells subjected to hypoxia/reoxygenation using a calcein/cobalt assay. Their ability to inhibit cell death was evaluated in cells subjected to hypoxia/reoxygenation by measuring lactate dehydrogenase (LDH) release, propidium iodide staining, and cell viability. The compound performing best in vitro was selected for in vivo efficacy evaluation in a mouse model of hepatic IRI.
Results:
The two compounds that showed the strongest inhibition of CypD PPIase activity and mPTP opening, C105 and C110, were selected. Their SR diastereoisomers carried the activity of the racemic mixture and exhibited mitoprotective properties superior to those of the known macrocyclic cyclophilin inhibitors cyclosporin A and alisporivir. C105SR was more potent than C110SR in inhibiting mPTP opening and prevented cell death in a model of hypoxia/reoxygenation. Finally, C105SR substantially protected against hepatic IRI in vivo by reducing hepatocyte necrosis and apoptosis.
Conclusions:
We identified a novel cyclophilin inhibitor with strong mitoprotective properties both in vitro and in vivo that represents a promising candidate for cellular protection in hepatic IRI.
Impact And Implications:
Hepatic ischaemia-reperfusion injury (IRI) is one of the main causes of morbidity and mortality during or after liver surgery. However, no effective therapies are available to prevent or treat this devastating syndrome. An attractive strategy to prevent hepatic IRI aims at reducing cell death by targeting mitochondrial permeability transition pore opening, a phenomenon regulated by cyclophilin D. Here, we identified a new small-molecule cyclophilin inhibitor, and demonstrated the enhanced mitoprotective and hepatoprotective properties of one of its diastereoisomers both in vitro and in vivo, making it an attractive lead compound for subsequent clinical development.
Insights
A new small-molecule cyclophilin inhibitor, C105SR, effectively blocks mitochondrial permeability transition pore opening. This compound shows significant promise for treating liver injury caused by ischaemia-reperfusion, offering new therapeutic potential.
Area of Science:
- Mitochondrial biology
- Pharmacology
- Hepatology
Background:
- Hepatic ischaemia-reperfusion injury (IRI) is a major cause of liver damage with no effective treatments.
- Mitochondrial permeability transition pore (mPTP) opening, regulated by cyclophilin D (CypD), is a key event in IRI-induced cell death.
- Inhibiting CypD is a promising strategy to protect against liver IRI.
Purpose of the Study:
- To identify and characterize novel small-molecule cyclophilin inhibitors (SMCypIs) for potential treatment of liver IRI.
- To evaluate the mitoprotective and hepatoprotective effects of these inhibitors both in vitro and in vivo.
Main Methods:
- Synthesized and evaluated derivatives of a parent SMCypI for CypD peptidyl-prolyl cis-trans isomerase (PPIase) activity.
- Assessed mitoprotective properties using mitochondrial swelling and calcium retention capacity assays.
- Evaluated mPTP inhibition and cell death prevention in hypoxia/reoxygenation models, followed by in vivo efficacy testing in a mouse hepatic IRI model.
Main Results:
- Two potent inhibitors, C105 and C110, and their SR diastereoisomers were identified, showing superior mitoprotective properties compared to existing inhibitors.
- The SR diastereoisomers, particularly C105SR, demonstrated strong inhibition of mPTP opening and prevented cell death in cellular models.
- C105SR significantly protected against hepatic IRI in vivo, reducing hepatocyte necrosis and apoptosis.
Conclusions:
- A novel cyclophilin inhibitor, C105SR, exhibits potent mitoprotective and hepatoprotective effects.
- This compound represents a promising therapeutic candidate for cellular protection in hepatic IRI.
- C105SR warrants further clinical development for treating liver IRI.
