Abstract
α-Aminoalkylphosphonate diaryl esters are potent, irreversible, and highly selective site-directed inhibitors of serine proteases. The structure of the phosphonate group resembles the transition state observed during a peptide bond hydrolysis and therefore phosphonates are referred as transition state analogues. They react with the hydroxyl group of the active site serine residue leading to formation of a stable enzyme-inhibitor complex. Moreover, incorporation of a peptidyl chain at the N-terminus as well as an introduction of electron withdrawing or electron donating substituents within the ester ring structure allows for a generation of specific inhibitors that react only with target serine protease. The great advantage of the aminophosphonate diaryl esters over other classes of inhibitors is their stability in aqueous solutions, no toxicity and lack of reactivity with cysteine, threonine, aspartyl and metalloproteinases. The above resulted in their application as convenient tools to study proteases function and activity using in vivo and in vitro assays of different pathological disorders (diabetes, cancer metastasis, pulmonary diseases or hypertension); to determine the cellular localization of the proteinases (activity based probes), to be used in proteomic approach or as the reactive antigens to develop a catalytic function within the antibodies binding site.
Herein we present the development of α-aminoalkylphosphonate diaryl esters as inhibitors of several serine proteases including dipeptidyl peptidase IV, cathepsin G, human neutrophil elastase, mast cell chymase and urokinase-type plasminogen activator. We have provided a historical perspective as well as a comprehensive report of the most recent studies in this field.
Keywords: α-aminophosphonates, serine proteases, protease inhibitor, activity-based probes, organophosphorous compounds.
Current Pharmaceutical Design
Title:Phosphonic Esters and their Application of Protease Control
Volume: 19 Issue: 6
Author(s): Renata Grzywa and Marcin Sienczyk
Affiliation:
Keywords: α-aminophosphonates, serine proteases, protease inhibitor, activity-based probes, organophosphorous compounds.
Abstract: α-Aminoalkylphosphonate diaryl esters are potent, irreversible, and highly selective site-directed inhibitors of serine proteases. The structure of the phosphonate group resembles the transition state observed during a peptide bond hydrolysis and therefore phosphonates are referred as transition state analogues. They react with the hydroxyl group of the active site serine residue leading to formation of a stable enzyme-inhibitor complex. Moreover, incorporation of a peptidyl chain at the N-terminus as well as an introduction of electron withdrawing or electron donating substituents within the ester ring structure allows for a generation of specific inhibitors that react only with target serine protease. The great advantage of the aminophosphonate diaryl esters over other classes of inhibitors is their stability in aqueous solutions, no toxicity and lack of reactivity with cysteine, threonine, aspartyl and metalloproteinases. The above resulted in their application as convenient tools to study proteases function and activity using in vivo and in vitro assays of different pathological disorders (diabetes, cancer metastasis, pulmonary diseases or hypertension); to determine the cellular localization of the proteinases (activity based probes), to be used in proteomic approach or as the reactive antigens to develop a catalytic function within the antibodies binding site.
Herein we present the development of α-aminoalkylphosphonate diaryl esters as inhibitors of several serine proteases including dipeptidyl peptidase IV, cathepsin G, human neutrophil elastase, mast cell chymase and urokinase-type plasminogen activator. We have provided a historical perspective as well as a comprehensive report of the most recent studies in this field.
Export Options
About this article
Cite this article as:
Grzywa Renata and Sienczyk Marcin, Phosphonic Esters and their Application of Protease Control, Current Pharmaceutical Design 2013; 19 (6) . https://dx.doi.org/10.2174/1381612811319060014
DOI https://dx.doi.org/10.2174/1381612811319060014 |
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
-
Hypovitaminosis D is Associated with Endothelial Dysfunction in Patients with Metabolic Syndrome
Current Vascular Pharmacology Sarcolemmal K<sub>ATP</sub> Channel Modulators and Cardiac Arrhythmias
Current Medicinal Chemistry Synthesis of Novel and Highly Functionalized Pyrimidine-5-carboxylate Derivatives and their Antimicrobial Evaluation
Letters in Drug Design & Discovery Oxytocin and Diabetes Mellitus: A Strong Biochemical Relation. Review
Current Diabetes Reviews Protective Effect of Dietary Potassium against Cardiovascular Damage in Salt-Sensitive Hypertension: Possible Role of its Antioxidant Action
Current Vascular Pharmacology Endogenous Cardioprotective Agents: Role in Pre and Postconditioning
Current Drug Targets Insulin Resistance, Obesity and the Metabolic Syndrome. Is there a Therapeutic Role for Endothelin-1 Antagonists?
Current Vascular Pharmacology Validation of a Solid Phase Extraction Procedure for Identification and Quantification of Cocaine and Metabolities in Meconium Using GC/MS
Current Pharmaceutical Analysis Systematic Review of the Role of Microparticles in Systemic Sclerosis
Current Rheumatology Reviews Genes, Environment, Intermediate Phenotypes, and the Pathogenesis of Diabetic Nephropathy
Current Pharmacogenomics β-Adrenomimetic Actions in the Hypotension and Vasodilatation Induced by a Chromatographic Active Fraction from Bidens pilosa L. (Asteraceae) in Mammals
Current Bioactive Compounds Effective Management of the Type 2 Diabetes Patient with Cardiovascular and Renal Disease: Secondary Prevention Strategies after a Myocardial Infarction
Current Diabetes Reviews Hypercholesterolemia and Endothelium Dysfunction: Role of Dietary Supplementation as Vascular Protective Agents
Current Vascular Pharmacology Medicinal Properties of Mangiferin, Structural Features, Derivative Synthesis, Pharmacokinetics and Biological Activities
Mini-Reviews in Medicinal Chemistry Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence
Current Pharmaceutical Design The General Practitioners Role in Promoting Physical Activity to Older Adults: A Review Based on Program Theory
Current Aging Science Antioxidants in Peripheral Arterial Disease
Current Drug Targets Cellular Mechanisms of Brain Injury and Cell Death
Current Pharmaceutical Design Recent Patents on Emerging Therapeutics for the Treatment of Glaucoma, Age Related Macular Degeneration and Uveitis
Recent Patents on Biomedical Engineering (Discontinued) Angiotensin Converting Enzyme-2: A Doorway for SARS-CoV-2
Coronaviruses