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
-
Addressing Alzheimer’s Disease and Cognitive Loss through Autophagy
Current Neurovascular Research Intracoronary Injection of Drugs to Treat No – Reflow Phenomenon and Microcirculatory Dysfunction
Cardiovascular & Hematological Agents in Medicinal Chemistry Hydroxysafflor Yellow a Promotes Angiogenesis in Rat Brain Microvascular Endothelial Cells Injured by Oxygen-glucose Deprivation/reoxygenation(OGD/R) through SIRT1-HIF-1α-VEGFA Signaling Pathway
Current Neurovascular Research Regulatory Mechanism miR-302a-3p/E2F1/SNHG3 Axis in Nerve Repair Post Cerebral Ischemic Stroke
Current Neurovascular Research Structural Changes in Alzheimers Disease Brain Microvessels
Current Alzheimer Research Platelets and Platelet Interaction with Progenitor Cells in Vascular Homeostasis and Inflammation
Current Vascular Pharmacology Treatment of Type 1 Diabetic Patients with Glucagon-Like Peptide-1 (GLP-1) and GLP-1R Agonists
Current Diabetes Reviews The Role of Calcium Handling Mechanisms in Reperfusion Injury
Current Pharmaceutical Design Subject Index to Volume 2
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Cellular Iron Homeostasis and Therapeutic Implications of Iron Chelators in Cancer
Current Pharmaceutical Biotechnology Renin Angiotensin System (RAS) and Immune System Profile in Specific Subgroups with COVID-19
Current Medicinal Chemistry Preclinical Profile of Bacopasides From Bacopa monnieri (BM) As An Emerging Class of Therapeutics for Management of Chronic Pains
Current Medicinal Chemistry Patent Selections
Recent Patents on Cardiovascular Drug Discovery Neuroprotective Role of Hypothermia in Hypoxic-ischemic Brain Injury: Combined Therapies using Estrogen
Current Neuropharmacology Structural Organization of the Regulatory Domain of Human 5- Lipoxygenase
Current Protein & Peptide Science Role of Oxidative Stress and Mitochondrial Dysfunction in Skeletal Muscle in Type 2 Diabetic Patients
Current Pharmaceutical Design The Role of PDE5-Inhibitors in Cardiopulmonary Disorders: From Basic Evidence to Clinical Development
Current Medicinal Chemistry Soluble Epoxide Hydrolase Inhibitors and Cardiovascular Diseases
Current Vascular Pharmacology Heat Shock Paradox and a New Role of Heat Shock Proteins and their Receptors as Anti-Inflammation Targets
Inflammation & Allergy - Drug Targets (Discontinued) Neuroprotective Role of Nanoparticles Against Alzheimer's Disease
Current Drug Metabolism