The specific aims of the research are to elucidate the interactions involved in the binding of heparin by peptides from the cell adhesion proteins fibronectin, laminin, vitronectin and thrombospondin. The initial research will focus on peptides from fibronectin, including peptides which bind to receptors on the surface of highly metastatic mouse melanoma cells. The research will involve studies of the parent peptides, peptide analogs, heparin and heparin- derived oligosaccharides. The objectives are to identify peptide and heparin motifs with a propensity for binding, to determine if binding involves site specific or delocalized electrostatic interactions, to determine the strength of binding in terms of binding constants and to characterize structural features of the heparin-peptide complexes. These objectives will be achieved using information obtained from nuclear magnetic resonance (NMR) spectroscopy. The motivation for the proposed research is that interruption of the cell adhesion process with synthetic peptides and/or oligosaccharides has potential as a therapeutic intervention (anti-adhesion therapy) in the development of diseases in which cell adhesion plays a critical role. For example, heparin binding fragments of cell adhesion proteins can inhibit the experimental metastasis of several tumors and heparin can inhibit the replication of human immunodeficiency virus type-1 (HIV-1). The long term objectives are to characterize, in detail at the molecular level, the interactions involved in the binding of peptides by heparin, starting with peptides from the cell adhesion domains of cell adhesion proteins. The knowledge to be gained is of clinical interest because it will provide a fundamental basis from which to design new synthetic peptides with even greater selectivity and specificity for use in anti- adhesion therapy.
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