The proposed research involves synthesis of a number of enzyme inhibitors, evaluation of their binding behavior, and correlation of this binding behavior with turnover of related substrates. Our intention is to develop effective strategies for the design of biologically active molecules and to provide insight into the relationship between inhibitor binding and enzyme mechanism. The inhibitors that are developed during the course of this work should be of medicinal importance in the areas of antitumor therapy, hypertension, and analgesia. The key elements to the program are the following: A. Cytidine Deaminase: The stereoselectivity of phosphapyrimidine inhibitors will be evaluated, whether they are transition state analogs will be determined, and the relationship between their slow-binding behavior and protein conformational changes will be examined. B. Zinc Peptidases: The correlation between phosphonamidate and transition state binding will be extended, the mechanism of slow-binding for these inhibitors will be elucidated, thermolysin and carboxypeptidase A will be compared in this respect, and a new class of phosphonamide inhibitors will be explored. C. Aspartic Peptidases: The nature of inhibition by a phosphorous-containing pepstatin analog will be elucidated, an explanation for its slow, two-step binding behavior will be sought, and phosphinamides and phosphonic acid inhibitors will be developed as more accurate transition state analogs for this class of peptidases. D. Glutamine-Dependent Amidotransferases: A general strategy for the inhibition of these enzymes will be developed and applied to the synthesis of multisubstrate analogs for carbamyl phosphate synthetase and phosphoribosyl pyrophosphate amidotransferase. E. Adenosine Deaminase: The phosphinate and phosphinamide analogs of coformycin will be synthesized as better mimics of the tetrahedral intermediate, their inhibition and slow-binding will be analyzed in relation to enzyme conformational changes. F. Sulfoxides as Inhibitors of Dehydrases: A program on suicide inhibitors based on enzyme-induced Pummerer-type reactions will be initiated (enzymes addressed: carnitine acetyltransferase, Beta-hydroxydecanoyl thiolester dehydrase, and mevalonate pyrophosphate decarboxylase).

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
9R01GM046627-14
Application #
3306062
Study Section
Biochemistry Study Section (BIO)
Project Start
1978-04-01
Project End
1995-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
14
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704