The allergic response is controlled primarily via IL-4 mediated expression of the IgE antibody. To prevent this reaction in non-threatening instances, we propose the development of a drug capable of binding the IL-4 receptor to preclude IL-4 binding, halting downstream actions. The development of the drug will be accomplished using molecular modeling to determine lead compounds, followed by the creation of a combinatorial library capable of randomizing six functional groups on the surface of the small molecule scaffold. The binding of these scaffolds to the IL-4 receptor will be monitored via mass spec analysis and surface plasmon resonance - high affinity compounds can be further explored to optimize binding to compete with IL-4 for the receptor binding site. Concurrently, the responsiveness of these scaffolds to the biological surroundings will be improved via introduction of a second binding site within the core of the scaffold. Binding of histamine, an important mediator of the allergic response, in this second site will be a necessary first step to activate the drug to bind the IL-4 receptor, preventing further expression of IgE. The successful regulation of IL-4 receptor binding using histamine as a mediator introduces the possibility of self-medicating drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM069321-02
Application #
6830718
Study Section
Special Emphasis Panel (ZRG1-F04 (20))
Program Officer
Marino, Pamela
Project Start
2003-11-16
Project End
2006-11-15
Budget Start
2004-11-16
Budget End
2005-11-15
Support Year
2
Fiscal Year
2005
Total Cost
$43,976
Indirect Cost
Name
University of Pennsylvania
Department
Biochemistry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104