The objective of the proposed research is to develop an understanding of the relationship between the substrate specificity of a serine protease and the active-site binding sequence of a potent inhibitor. Serine proteases are ubiquitous in biology and may play a role in a number of pathogenic states including thrombotic disorders, hypertension, osteoarthritis, chronic degenerative disorders and cancer. A combinatorial library of fluorogenic synthetic peptide substrates will be used to elucidate the preferred substrate sequence for a series of cancer-related serine proteases. From these studies, insights into the structural determinants of protease specificity will be obtained along with information about the biological targets of specific proteases. Potent inhibitors of individual proteases will be developed by combinatorially redesigning the active- site binding domain of the dimeric protease inhibitor ecotin using phage display technologies. A knowledge of the extended protein-protein interactions that are involved in substrate or inhibitor recognition will further our understanding of the structure-function relationship among proteases and their inhibitors. The in vivo functions of cancer-related serine proteases will begin to be elucidated and potent inhibitors with potential therapeutic value will be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32GM063459-01
Application #
6340082
Study Section
Special Emphasis Panel (ZRG1-BIO (20))
Program Officer
Marino, Pamela
Project Start
2001-08-01
Project End
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
1
Fiscal Year
2001
Total Cost
$33,260
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143