The availability of efficient and selective inhibitors of certain serine proteases would provide a new approach to the regulation of certain physiological functions (fertilization, blastocyst implantation, tissue remodeling) and the treatment of certain pathologies (emphysema, adult respiratory distress syndrome, glomerulonephritis, arthritis, inflammatory disorders, tumor invasion and metastasis). We have previously prepared halo enol lactones that appear to act, through a two-step acylation- alkylation sequence, as mechanism-based inactivators of the serine protease chymotrypsin. We are now planning to study the mechanistic details of the inactivation process, to determine what chemical species are involved and what residue is the site of alkylation; furthermore, we will utilize computer graphics- molecular modeling to rationalize relationships between inactivator structure and inactivating efficiency and potency, and to improve in the design of new inhibitors. Specific efforts will be made: (1) to prepare certain new lactones that will be used to investigate further an inactivation burst kinetic model, (2) to prepare lactones specifically labeled with C-13 as NMR spectroscopic probes to follow the chemical changes at specific atoms in the lactone during the sequence of steps leading to inactivation, (3) to develop enol lactone precursors of reactive Michael acceptors, (4) to develop inhibitors based on slow deacylation due to a predicted twisting of the acyl enzyme observed in certain beta-substituted lactones, and (5) to develop fluoroketones as transition state inhibitors of high potency. The compounds that demonstrate the best inhibitory properties towards chymotrypsin will also be prepared in forms that should make them suitable as inhibitor for elastase, trypsin, plasmin and plasminogen activator.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK027526-10
Application #
3228354
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1980-08-01
Project End
1992-07-31
Budget Start
1990-08-01
Budget End
1992-07-31
Support Year
10
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820