The central objective of this Project is to use the structures of the gp120/CD3=4 complex and of D1-D4 CD4 to identify topographical regions of these proteins which when transplanted into miniproteins or mimicked in peptides and small molecules will generate new ligands with which to antagonise the interaction of human cells with HIV-1, the human immunodeficiency virus responsible for AIDS. T-cell docking and entry by HIV-1, a major route of cell infiltration and resultant infection in AIDS, is driven by specific recognition of the T-cell surface protein CD4 with the HIV envelope protein gp120. The crystallographic structure of CD4 is known, and that of its complex with gp120 is closed at hand. Structural components in both protein partners have been identified which are proposed to play key roles in CD4- gp120 recognition. The advancing high resolution structural understanding of the protein participants in virus-cell recognition together with the advancing technology of mimetics design now make it possible to combine structure determination, modeling, miniprotein engineering and organic synthesis to design new antagonists for AIDS.
The specific aims of this proposal are: (1) Identify binding sites in the CD4/gp120 interface by computational modeling of existing high resolution structures; and (2) Utilize key structural elements as determined from high resolution structure; modeling and miniprotein, constrained peptide and nonpeptide scaffolds to design small molecule CD4 antagonists for AIDS. The ultimate goal of this grant proposal is to produce a small molecule capable of antagonizing the interaction of CD4 and gp120.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM056550-04
Application #
6336548
Study Section
Project Start
2000-08-01
Project End
2001-07-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
4
Fiscal Year
2000
Total Cost
$151,228
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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