The long term goal of this project is to discover and develop new therapeutic agents for graft-versus- host disease (GVHD) which is a major complication after allogeneic bone marrow transplantation (BMT) in patients with leukemia and other oncologic disorders. In addition, we intend to use this project as a model to develop a general structure-based approach to discover small molecular inhibitors of protein-protein interactions involved in T cell stimulatory pathways. The underlying hypothesis of our research is that the interaction between the CD4 protein and the major histocompatibility complex (MHC) class II protein is critical for T cell activation, and therefore small molecules interrupting such CD4-MHC class II interaction could be used as effective immunosuppressive agents. In a series of recent studies, we identified a CD4 surface pocket implicated in CD4-MHC class II interaction and T cell activation. Using a computer-based technique to screen (150,000 small organic compounds, we discovered a group of novel ligands of the CD4 surface pocket that could inhibit CD4 function. Among them, the most potent lead compound TJU103 was shown to specifically bind to the CD4 surface pocket, block CD4 interaction with MHC class II, and significantly inhibit T cell activation. We demonstrated that TJU103 is highly effective in vivo in murine GVHD. Furthermore, we found that TJU103 is orally active, not toxic, and highly selective for CD4- mediated immune response. These findings strongly suggested that TJU103 is a promising lead compound for the development of a new class of immunotherapeutics for GVHD in cancer patients undergoing BMT. Here we propose to apply an interdisciplinary approach combining organic synthesis, biological studies, and computer modeling to study the structure-activity relationship of TJU103 and develop analogs with higher potency and optimized pharmacological profiles for further pre-clinical studies and eventually clinical trials in humans. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
5R43AI068383-02
Application #
7184327
Study Section
Special Emphasis Panel (ZRG1-IMM-G (10))
Program Officer
Prograis, Lawrence J
Project Start
2006-02-15
Project End
2009-07-31
Budget Start
2007-02-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$387,982
Indirect Cost
Name
Chemokine Pharmaceutical, Inc.
Department
Type
DUNS #
154193663
City
San Diego
State
CA
Country
United States
Zip Code
92121