Abstract
The calpains represent a well-conserved family of calcium-dependent cysteine proteases. They consist of several ubiquitous and tissue specific isoforms and exhibit broad substrate specificity influencing many aspects of cell physiology including migration, proliferation and apoptosis. Calpain activity in vivo is tightly regulated by its natural endogenous inhibitor calpastatin. Calpastatin specifically inhibits calpain and not other cysteine proteases by interaction with several sites on the calpain molecule. Inappropriate regulation of the calpain-calpastatin proteolytic system is associated with several important human pathological disorders including muscular dystrophy, cancer, Alzheimers disease, neurological injury, ischaemia/reperfusion injury, atherosclerosis, diabetes and cataract formation. Recent advances in elucidating the tertiary structures of calpain 2 and its regulatory domain calpain 4, together with identification of new modes of regulating calpain activity provide new opportunities for the design of novel calpain inhibitors. Several classes of inhibitors, including peptidyl epoxide, aldehyde, and ketoamide inhibitors, targeting the active site have proven effective against the calpains and are in the process of evaluation in animal models of human disease. However, a major limitation to the clinical use of such inhibitors is their lack of specificity among cysteine proteases and other proteolytic enzymes. The development of a new class of calpain inhibitors that interact with domains outside of the catalytic site of calpain may provide greater specificity and therapeutic potential.
Keywords: Calpain, calpastatin, signal transduction, migration, proliferation, apoptosis, cancer, neurological injury
Current Pharmaceutical Design
Title: Calpain Inhibition: A Therapeutic Strategy Targeting Multiple Disease States
Volume: 12 Issue: 5
Author(s): N. O. Carragher
Affiliation:
Keywords: Calpain, calpastatin, signal transduction, migration, proliferation, apoptosis, cancer, neurological injury
Abstract: The calpains represent a well-conserved family of calcium-dependent cysteine proteases. They consist of several ubiquitous and tissue specific isoforms and exhibit broad substrate specificity influencing many aspects of cell physiology including migration, proliferation and apoptosis. Calpain activity in vivo is tightly regulated by its natural endogenous inhibitor calpastatin. Calpastatin specifically inhibits calpain and not other cysteine proteases by interaction with several sites on the calpain molecule. Inappropriate regulation of the calpain-calpastatin proteolytic system is associated with several important human pathological disorders including muscular dystrophy, cancer, Alzheimers disease, neurological injury, ischaemia/reperfusion injury, atherosclerosis, diabetes and cataract formation. Recent advances in elucidating the tertiary structures of calpain 2 and its regulatory domain calpain 4, together with identification of new modes of regulating calpain activity provide new opportunities for the design of novel calpain inhibitors. Several classes of inhibitors, including peptidyl epoxide, aldehyde, and ketoamide inhibitors, targeting the active site have proven effective against the calpains and are in the process of evaluation in animal models of human disease. However, a major limitation to the clinical use of such inhibitors is their lack of specificity among cysteine proteases and other proteolytic enzymes. The development of a new class of calpain inhibitors that interact with domains outside of the catalytic site of calpain may provide greater specificity and therapeutic potential.
Export Options
About this article
Cite this article as:
Carragher O. N., Calpain Inhibition: A Therapeutic Strategy Targeting Multiple Disease States, Current Pharmaceutical Design 2006; 12 (5) . https://dx.doi.org/10.2174/138161206775474314
DOI https://dx.doi.org/10.2174/138161206775474314 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read 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
-
Therapeutic Applications of Human Heme Oxygenase Gene Transfer and Gene Therapy
Current Pharmaceutical Design The Redox Regulation of Thiol Dependent Signaling Pathways in Cancer
Current Pharmaceutical Design Calcium Sensitizers in Cardiac Surgery: Who, When, How and Why?
Current Vascular Pharmacology Myocardial Expression of TNF-α, IL-1β, IL-6, IL-8, IL-10 and MCP-1 After a Single MDMA Dose Administered in a Rat Model
Current Pharmaceutical Biotechnology Clinical Applications of Cardiac Multi-Slice Computed Tomography
Current Medical Imaging Stem Cells in Cardiovascular Regeneration: From Preservation of Endogenous Repair to Future Cardiovascular Therapies
Current Pharmaceutical Design Rational Basis for Nutraceuticals in the Treatment of Glaucoma
Current Neuropharmacology Development of Monoclonal Antibodies that Inhibit Platelet Adhesion or Aggregation as Potential Anti-Thrombotic Drugs
Cardiovascular & Hematological Disorders-Drug Targets Potential Therapeutic Targeting of Platelet-Mediated Cellular Interactions in Atherosclerosis and Inflammation
Current Medicinal Chemistry Subject Index to Volume 3
Current Drug Targets - Cardiovascular & Hematological Disorders Beneficiary and Adverse Effects of Phytoestrogens: A Potential Constituent of Plant-based Diet
Current Pharmaceutical Design Actions of Rho-Kinase Inhibitors in Cardiovascular Diseases
Current Enzyme Inhibition Establishing Maternal Tolerance: The Role of Regulatory T Cells (Tregs) in Pregnancy and Pathophysiology of Preeclampsia
Current Women`s Health Reviews Improved Anti-inflammatory Activity and Potential Cytoprotective Properties of Tolfenamic Acid, Naproxen and Indomethacin Derivatives
Letters in Drug Design & Discovery Recent Progresses in Application of Fullerenes in Cosmetics
Recent Patents on Biotechnology Computational Biological Analysis Reveals a Role for Nitric Oxide Synthase and Adiponectin in the Pathobiology of Insulin Resistance Syndrome and Coronary Artery Disease
Current Nutrition & Food Science Brainstem Neuropeptides and Vagal Protection of the Gastric Mucosal Against Injury: Role of Prostaglandins, Nitric Oxide and Calcitonin-Gene Related Peptide in Capsaicin Afferents
Current Medicinal Chemistry Immunosuppressive Drugs in HIV Disease
Current Topics in Medicinal Chemistry Targeting the p53 Pathway of Apoptosis
Current Pharmaceutical Design Functional Role of ADP-Ribosyl-Acceptor Hydrolase 3 in poly(ADPRibose) Polymerase-1 Response to Oxidative Stress
Current Protein & Peptide Science