Abstract
Three alpha-aminoboronic acid-containing analogs of good peptide substrates for serine proteases were synthesized, MeO-Suc-Ala-Ala-Pro-boro-Phe-OH, MeO-Suc-Ala-Ala-Pro-boro-Ala-OH, and MeO-Suc-Ala-Ala-Pro-boro-Val-OH. They were effective inhibitors of chymotrypsin, cathepsin G, and both leukocyte and pancreatic elastase at nanomolar concentrations (0.10-20 nM). Except for cathepsin G, inhibition was not simply competitive, but showed kinetic properties corresponding to the mechanism for slow-binding inhibition, i.e. E + I in equilibrium EI in equilibrium EI*, where EI and EI* are enzyme-inhibitor complexes and EI* is more stable than EI. This type of inhibition has not been observed previously for synthetic inhibitors or serine proteases and in this study it was observed only for peptide boronic acids which satisfy the primary specificity requirements of the protease.
Highlights
The approachwe have taken in a search for more selective and effective inhibitors of the leukocyte proteases pancreatic elastase and chymotrypsin has been to prepare peptide boronic acids
Leukocyte elastase and cathepsin G are serine proteases shown to be inhibited by aromatic boronic acids (Koehler and associated with the granular fraction of polymorphonuclear Lienhard, 1971;Lindquist and Terry1,974).The crystal strucleukocyteswhichhydrolyze multiple bonds of protein sub- ture of subtilisin complexed to either phenylethane boronic strates
-20 “C. Stock solutions of leukocyte elastase (1.0 mg ml-I) were prepared in 0.05 M sodium acetate buffer, pH 5.5, containing 0.40 M The synthesis of amino boronic acids is described in Appendix I1 and
Summary
Vol 259, No 24, Issue of December 25, pp. 15106-15114,1984 Printed m U .S.A. Inhibition of the Serine Proteases Leukocyte Elastase, Pancreatic Elastase, CathepsinG, and Chymotrypsin by Peptide Boronic Acids*. EmIe+chaEnPism, wfhoerreslEowI -abnidndEiIn*g inare enzyme-inhibitor complexes and EI* is more stable than EI This type of inhibition has not been observed previously for synthetic inhibitors or serine proteases and inthis study itwas observed only for peptide boronic acidswhichsatisfythe primary specificity requirements of theprotease. The approachwe have taken in a search for more selective and effective inhibitors of the leukocyte proteases pancreatic elastase and chymotrypsin has been to prepare peptide boronic acids. This group of compoundstakesadvantage of binding in thPeI-PS sites (using the nomenclatureof Schechter and Berger, 1967) and of the binding of the boronic acid which can potentially act as a “transition state analog.”.
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