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.
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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 |
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