Abstract
Protease activated receptors (PARs) are a category of G-protein coupled receptors (GPCRs) implicated in the progression of a wide range of diseases, including thrombosis, inflammatory disorders, and proliferative diseases. Signal transduction via PARs proceeds via an unusual activation mechanism. Instead of being activated through direct interaction with an extracellular signal like most GPCRs, they are self-activated following cleavage of their extracellular N-terminus by serine proteases to generate a new receptor N-terminus that acts as an intramolecular ligand by folding back onto itself and triggering receptor activation. Short synthetic peptides corresponding to this newly exposed N-terminal tethered ligand can activate three of the four known PARs in the absence of proteases, and such PAR activating peptides (PAR-APs) have served as templates for agonist/antagonist development. In fact much of the evidence for involvement of PARs in diseases has relied upon use of PAR-APs, often of low potency and uncertain selectivity. This review summarizes current structures of PAR agonists and antagonists, the need for more selective and more potent PAR ligands that activate or antagonize this intriguing class of receptors, and outlines the background relevant to PAR activation, assay methods, and physiological properties anticipated for PAR ligands.
Keywords: GPCR, PAR, protease, review, agonist, antagonist, thrombin, trypsin
Current Medicinal Chemistry
Title: Agonists and Antagonists of Protease Activated Receptors (PARs)
Volume: 13 Issue: 3
Author(s): Grant D. Barry, Giang T. Le and David P. Fairlie
Affiliation:
Keywords: GPCR, PAR, protease, review, agonist, antagonist, thrombin, trypsin
Abstract: Protease activated receptors (PARs) are a category of G-protein coupled receptors (GPCRs) implicated in the progression of a wide range of diseases, including thrombosis, inflammatory disorders, and proliferative diseases. Signal transduction via PARs proceeds via an unusual activation mechanism. Instead of being activated through direct interaction with an extracellular signal like most GPCRs, they are self-activated following cleavage of their extracellular N-terminus by serine proteases to generate a new receptor N-terminus that acts as an intramolecular ligand by folding back onto itself and triggering receptor activation. Short synthetic peptides corresponding to this newly exposed N-terminal tethered ligand can activate three of the four known PARs in the absence of proteases, and such PAR activating peptides (PAR-APs) have served as templates for agonist/antagonist development. In fact much of the evidence for involvement of PARs in diseases has relied upon use of PAR-APs, often of low potency and uncertain selectivity. This review summarizes current structures of PAR agonists and antagonists, the need for more selective and more potent PAR ligands that activate or antagonize this intriguing class of receptors, and outlines the background relevant to PAR activation, assay methods, and physiological properties anticipated for PAR ligands.
Export Options
About this article
Cite this article as:
Barry D. Grant, Le T. Giang and Fairlie P. David, Agonists and Antagonists of Protease Activated Receptors (PARs), Current Medicinal Chemistry 2006; 13 (3) . https://dx.doi.org/10.2174/092986706775476070
DOI https://dx.doi.org/10.2174/092986706775476070 |
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
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...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
- 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
-
Nitric Oxide Signaling and the Cross Talk with Prostanoids Pathways in Vascular System
Medicinal Chemistry Nicotinic Acetylcholine Receptor Agonists: A Potential New Class of Analgesics
Current Topics in Medicinal Chemistry Excitotoxic Mechanisms in Non-Motor Dysfunctions and Levodopa- Induced Dyskinesia in Parkinson's Disease: The Role of the Interaction Between the Dopaminergic and the Kynurenine System
Current Medicinal Chemistry Are the Antioxidant Properties of Carvedilol Important for the Protection of Cardiac Mitochondria?
Current Vascular Pharmacology Nebivolol: More Than a Highly Selective Beta Blocker
Recent Patents on Cardiovascular Drug Discovery Biochemical Aspects of Nitric Oxide
Current Pharmaceutical Design Aryltetralin-type Lignan of Podophyllum: A Comprehensive Review
The Natural Products Journal The Rapidly Changing Composition of the Global Street Drug Supply and its Effects on High-risk Groups for COVID-19
Current Psychopharmacology Cardiovascular-Related
Current Bioactive Compounds Treatment of Diabetic Foot Ulcers
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Managing Side Effects on Ocular Surface Caused by Glaucoma Eye Drops
Current Medicinal Chemistry Sedation in PACU: Indications, Monitoring, Complications
Current Drug Targets Inotropic and Vasoactive Drugs in Pediatric ICU
Current Drug Targets Geriatric Depression - Review for Primary Care
Current Psychiatry Reviews Pharmacogenetics of Statins Therapy
Recent Patents on Cardiovascular Drug Discovery “The Future Magic Bullet”: A Review of Pharmacological Activities of Ethyl Pyruvate and its Derivatives
Current Drug Therapy Hypertension in Hemodialysis Patients
Current Hypertension Reviews Hypersensitivity Reactions to Neuromuscular Blocking Agents
Current Pharmaceutical Design Inflammation-Mediating Proteases: Structure, Function in (Patho) Physiology and Inhibition
Protein & Peptide Letters Isolation and Identification of an Angiotensin-I Converting Enzyme Inhibitory Peptide from Yeast (Saccharomyces cerevisiae)
Current Analytical Chemistry