) CD4 is a glycoprotein expressed on the T-cell surface that consists of four extracellular domains (D1-D4) and plays an important role in regulating T cell functions. We have developed a cyclic heptapeptide, 802-2, that interferes with CD4-mediated functions, and new analogs targeted to the same portion of the D1 domain of the CD4 molecule. The 802-2 peptide is about to enter clinical trials for the prevention of graft versus host disease (GvHD) (in Project 3 of this application). Recent X-ray crystallographic, genetic, and peptide studies by other laboratories and our own collectively suggest that D3D4 domains are critical for CD4 function (dimerization and binding to MHC class II molecules). The major goal of this project is to understand the biochemical and structural basis of the function of the 802-2 peptide and to develop new analogs of 802-2 with optimized therapeutic profiles for the prevention of GvHD in bone marrow transplantation. In addition, we will study other D1 organic inhibitors and explore the structure-function relationships of CD4 D3 and D4 domains as new targets for rational drug design. Contrary to D1D2, D3D4 domains are largely unexplored and represent an entirely new area. Since the 802-2 peptide is our current lead compound for phases I & II clinical trials and the central focus of this program project, we will mainly concentrate on biochemical and X-ray co-crystal studies of this peptide and new lead compounds in complex with D1 receptor sites, and we will subsequently use such information to optimize 802-2-related analogs as clinically relevant drugs. Specifically, we will (1) conduct biochemical and X-ray crystallographic studies of lead compound-receptor interactions, (2) develop new analogs of the current lead 802-2 peptide with optimized biological and clinical profiles, (3) Characterize structure-function relationships of D3D4 domains using both synthetic peptides and organic compounds as biological probes. These studies are expected to enhance understanding of CD4-ligand interactions, and to result in the production of more effective reagents in the prevention/treatment of GvHD.
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