Benzisothiazolinone- 1,1 -dioxides are potent, time-dependent, reversible inhibitors of human leukocyte elastase (HLE) that demonstrate the ability to inhibit HLE catalyzed degradation of insoluble elastin. A stoichiometry of 1.4 to 1.47 equivalents per mole of enzyme indicates that these compounds are efficient inhibitors of HLE. The proposed mechanism of HLE inhibition has been investigated and the data are consistent with acylation of the active site serine followed by elimination of the leaving group to form a reactive sulfonyl imine intermediate. The reactive intermediate can undergo hydration followed by deacylation or it can react with an enzyme nucleophile to form a stable enzyme-inhibitor complex that slowly reactivates. Initial velocities in the presence and absence of inhibitor are identical, establishing that the reversible formation of a Michaelis complex does not occur prior to covalent interaction between the enzyme and inhibitor. The leaving group is released in a kinetically competent step without an induction period. The lack of a secondary deuterium isotope effect on inactivation kinetics is consistent with rate limiting forward acylation. Reactivation is independent of leaving group variations, suggesting the formation of a common enzyme-inhibitor complex and a common reactivation pathway through the same rate determining step. The product of reactivation is the 4-isopropyl-6- methoxysaccharin. Initially, 30% forms within 5 minutes while the remainder forms slowly over 4 days. This is consistent with partitioning between reactivation and crosslinking the enzyme active site serine and histidine. Even the crosslinked enzyme has an important reactivation pathway whereby the enzyme regains full activity. Thus, this class of compounds may offer several advantages over other types of HLE inhibitors as potential therapeutic agents in the treatment of inflammatory pulmonary diseases.

Library of Congress Subject Headings

Leucocyte elastase--Inhibitors--Research; Enzyme inhibitors--Research; Enzyme inhibitors--Therapeutic use--Research

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School of Chemistry and Materials Science (COS)


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