Abstract
The mitochondrial permeability transition (MPT) plays an important role in damage-induced cell death, and agents inhibiting the MPT may have a therapeutic potential for treating human conditions such as ischemia / reperfusion injury, trauma, and neurodegenerative diseases. The mitochondrial matrix protein, cyclophilin D (CYP D), a member of a family of highly homologous peptidylprolyl cis-trans isomerases (PPIases), plays a decisive role in MPT, being an integral constituent of the MPT pore. Other putative MPT pore proteins include the adenine nucleotide translocator (ANT) and the voltage-dependent anion channel (VDAC). In an alternative model, the MPT pore is formed by clusters of misfolded membrane proteins outlining aqueous channels that are regulated by CYP D and other chaperone-like proteins. Like cyclophilin A (CYP A) and other cyclophilin family members, CYP D is targeted by the immunosuppressant cyclosporin A (CsA). CsA is cytoprotective in many cellular and animal models, but protection may result from either inhibition of the MPT through an interaction with CYP D or inhibition of calcineurin-mediated dephosphorylation of BAD through an interaction with CYP A. The relevance of MPT inhibition by CsA for its cytoprotective effects is well documented in many cellular models. Mechanisms of action in vivo are more difficult to define, and accordingly the evidence is as yet less compelling in in vivo animal models of ischemia / reperfusion injury, trauma and neurodegenerative diseases. Notwithstanding, CYP D is a drug target of high interest. Structural considerations suggest feasibility of designing CYP D ligands without immunosuppressant properties. This is highly desirable, since they have the potential of being useful therapeutic agents in a variety of disease states. It might be a tougher challenge to obtain compounds specific for CYP D vs. other cyclophilins, and / or of small molecular weight, allowing brain penetration to make them suitable for treating neurodegenerative diseases.
Keywords: cyclophilin d, peptidylprolyl cis-trans isomerases, adenine nucleotide translocator, mpt pore
Current Medicinal Chemistry
Title: Cyclophilin D as a Drug Target
Volume: 10 Issue: 16
Author(s): Peter C. Waldmeier, Kaspar Zimmermann, Ting Qian, Marina Tintelnot-Blomley and John J. Lemasters
Affiliation:
Keywords: cyclophilin d, peptidylprolyl cis-trans isomerases, adenine nucleotide translocator, mpt pore
Abstract: The mitochondrial permeability transition (MPT) plays an important role in damage-induced cell death, and agents inhibiting the MPT may have a therapeutic potential for treating human conditions such as ischemia / reperfusion injury, trauma, and neurodegenerative diseases. The mitochondrial matrix protein, cyclophilin D (CYP D), a member of a family of highly homologous peptidylprolyl cis-trans isomerases (PPIases), plays a decisive role in MPT, being an integral constituent of the MPT pore. Other putative MPT pore proteins include the adenine nucleotide translocator (ANT) and the voltage-dependent anion channel (VDAC). In an alternative model, the MPT pore is formed by clusters of misfolded membrane proteins outlining aqueous channels that are regulated by CYP D and other chaperone-like proteins. Like cyclophilin A (CYP A) and other cyclophilin family members, CYP D is targeted by the immunosuppressant cyclosporin A (CsA). CsA is cytoprotective in many cellular and animal models, but protection may result from either inhibition of the MPT through an interaction with CYP D or inhibition of calcineurin-mediated dephosphorylation of BAD through an interaction with CYP A. The relevance of MPT inhibition by CsA for its cytoprotective effects is well documented in many cellular models. Mechanisms of action in vivo are more difficult to define, and accordingly the evidence is as yet less compelling in in vivo animal models of ischemia / reperfusion injury, trauma and neurodegenerative diseases. Notwithstanding, CYP D is a drug target of high interest. Structural considerations suggest feasibility of designing CYP D ligands without immunosuppressant properties. This is highly desirable, since they have the potential of being useful therapeutic agents in a variety of disease states. It might be a tougher challenge to obtain compounds specific for CYP D vs. other cyclophilins, and / or of small molecular weight, allowing brain penetration to make them suitable for treating neurodegenerative diseases.
Export Options
About this article
Cite this article as:
Waldmeier C. Peter, Zimmermann Kaspar, Qian Ting, Tintelnot-Blomley Marina and Lemasters J. John, Cyclophilin D as a Drug Target, Current Medicinal Chemistry 2003; 10 (16) . https://dx.doi.org/10.2174/0929867033457160
DOI https://dx.doi.org/10.2174/0929867033457160 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Heart Failure Models: Traditional and Novel Therapy
Current Vascular Pharmacology Heat Shock Proteins - Two Sides of a Coin
Current Cardiology Reviews Inducers of Heme Oxygenase-1
Current Pharmaceutical Design Repetitive Transient Phosphodiesterase-3 Inhibition Eliminates Non-ischemic Cardiac Remodeling and Failure
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Potential Application of Biliverdin Reductase and its Fragments to Modulate insulin/IGF-1/MAPK/PI3-K Signaling Pathways in Therapeutic Settings
Current Drug Targets Hypoxia-Inducible Factor-1α Contributes to Brain Edema after Stroke by Regulating Aquaporins and Glycerol Distribution in Brain
Current Neurovascular Research Involvement of Leukotriene Pathway in the Pathogenesis of Ischemia- Reperfusion Injury and Septic and Non-Septic Shock
Current Vascular Pharmacology FTY720 (Fingolimod) Ameliorates Brain Injury through Multiple Mechanisms and is a Strong Candidate for Stroke Treatment
Current Medicinal Chemistry Endothelial Remodelling and Intracellular Calcium Machinery
Current Molecular Medicine Minocycline Repurposing in Critical Illness: Focus on Stroke
Current Topics in Medicinal Chemistry Transcriptional Regulation of the Heme Oxygenase-1 Gene Via the Stress Response Element Pathway
Current Pharmaceutical Design Human Use of Leucoselect® Phytosome® with Special Reference to Inflammatory- Allergic Pathologies in Frail Elderly Patients
Current Pharmaceutical Design Beneficial Neurobiological Effects of Melatonin Under Conditions of Increased Oxidative Stress
Current Medicinal Chemistry - Central Nervous System Agents Is the Therapeutic Potential of Stem Cells for Myocardial Regeneration Limited by Proarrhythmic Effects?
Current Cardiology Reviews Molecular Pathways of Endothelial Cell Activation for (Targeted) Pharmacological Intervention of Chronic Inflammatory Diseases
Current Vascular Pharmacology Oxidative Stress Genes, Antioxidants and Coronary Artery Disease in Type 2 Diabetes Mellitus
Cardiovascular & Hematological Agents in Medicinal Chemistry Inhibition of Procarcinogen Activating Enzyme CYP1A2 Activity and Free Radical Formation by Caffeic Acid and its Amide Analogues
Drug Metabolism Letters Drugs Interfering with Apoptosis in Breast Cancer
Current Pharmaceutical Design Restoration of the Attenuated Neuroprotective Effect of Ischemic Postconditioning in Diabetic Mice by SGLT Inhibitor Phlorizin
Current Neurovascular Research Resveratrol Targets in Inflammation
Endocrine, Metabolic & Immune Disorders - Drug Targets