The objectives of this research are to characterize, in detail at the molecular level, the interactions involved in the binding of heparin and heparin-derived oligosaccharides by synthetic peptides. This study will focus on the binding interactions between heparin, and heparin-derived tetra- and hexasaccharides with peptides which have predominately alpha-helix conformations. The structural characterization of the oligosaccharides and the peptides prior to binding, and their subsequent binding interactions will be studied by Nuclear Magnetic Resonance Spectroscopy (NMR), Circular Dichroism Spectrometry (CD), and molecular modeling. These results are of fundamental interest because they will increase our knowledge of the structural and conformational features of heparin, and of the types of interactions involved in the binding of peptides and oligosaccharides to cell adhesion sites. This knowledge is necessary for the rational design of peptide drug candidates for antiadhesion therapies, i.e. therapies in which critical cell adhesion steps are inhibited by competitive binding of peptides to cell adhesion sites on the cell surface or of heparin to cell adhesion sites of the extracellular matix. Cell adhesion is a critical step in the development of many diseases including arthritis, metastatic cancer, and diseases in which viruses and parasites invade cells. Intervention at the cell adhesion steps with peptides or oligosaccharides which bind to cell adhesion sites, is one approach to the prevention and treatment of these diseases.
