Cell adhesion plays a critical role in the development of many diseases, including arthritis, metastatic cancer and diseases caused by the invasion of cells by viruses and bacteria. Cell adhesion is mediated by interactions between receptors on the cell surface and ligands of the extracellular matrix or other surfaces. Receptor molecules include the glycosaminoglycan part of proteoglycans such as heparan sulfate proteoglycan and ligands include cell adhesion proteins such as fibronectin. 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 metastatic 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 which have the amino acid sequences of heparin-binding domains of cell adhesion proteins and other 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 and for neutralization of the anticoagulant activity of heparin.
The specific aims of the research 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 the 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 high field nuclear magnetic resonance (NMR) spectroscopy experiments.
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