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Mechanism‐based isocoumarin inhibitors for serine proteases: Use of active site structure and substrate specificity in inhibitor design
Author(s) -
Powers James C.,
Kam ChihMin,
Narasimhan Lakshmi,
Oleksyszyn Joszef,
Hernandez Maria A.,
Ueda Toshihisa
Publication year - 1989
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.240390105
Subject(s) - isocoumarin , proteases , chemistry , kallikrein , biochemistry , serine protease , serine , serine proteinase inhibitors , active site , enzyme inhibitor , enzyme , pancreatic elastase , isocoumarins , stereochemistry , elastase , protease , catalysis
Abstract Isocoumarins are potent mechanism‐based heterocyclic irreversible inhibitors for a variety of serine proteases. Most serine proteases are inhibited by the general serine protease inhibitor 3,4‐dichloroisocoumarin, whereas isocoumarins containing hydrophobic 7‐acylamino groups are potent inhibitors for human leukocyte elastase and those containing 7‐alkylureidogroups are inhibitors for porcine pancreatic elastase. Isocoumarins containing basic side chains that resemble arginine are potent inhibitors for trypsin‐like enzymes. A number of 3‐alkoxy‐4‐chloro‐7‐guanidinoisocoumarins are potent inhibitors of bovine thrombin, human factor Xa, human factor XIa, human factor XIIa, human plasma kallikrein, porcine pancreatic kallikrein, and bovine trypsin. Another cathionic derivative, 4‐chloro‐3‐(2‐isothiureidoethoxy) isocoumarin, is less reactive toward many of these enzymes but is an extremely potent inhibitor of human plasma kallikrein. Several guanidinoisocoumarins have been tested as anticoagulants in human plasma and are effective at prolonging the prothrombin time. The mechanism of inhibition by this class of heterocyclic inactivators involves formation of an acyl enzyme by reaction of the active site serine with the isocoumarin carbonyl group. Isocoumarins with 7‐amino or 7‐guanidino groups will then decompose further to quinone imine methide intermediates, which react further with an active site residue (probably His‐57) to form stable inhibited enzyme derivatives. Isocoumarins should be useful in further investigations of the physiological function of serine proteases and may have future therapeutic utility for the treatment of emphysema and coagulation disorders.