NEW STRATAGIES FOR FORMATION OF PEPTIDE BETA-SHEETS

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The three-dimensional structures of peptides and proteins governs their biological functions. It is not generally possible to predict these structures, and only limited progress has been made toward controlling structure in artificial peptides and proteins. The creation of beta- sheets has proven particularly challenging, since contacts between remote residues are involved. At present, there are no adequate means for creating soluble, multiple-stranded B-sheets, and this area of protein design holds tremendous potential for new discoveries. The development of general strategies for the creation of protein secondary structures would facilitate the design of pharmacologically useful mimics of biologically active peptides and proteins. This proposal aims to develop three new strategies for the creation of beta-sheets in peptide derivatives. In these strategies, enforced proximity, intramolecular hydrogen bonding, and hydrophobic interactions work in conjunction to induce the formation of beta-sheets. The first strategy uses an oligourea template to hold strands of peptides in proximity permit the formation of parallel and antiparallel beta-sheets consisting of two or more strands of peptides. The second uses a rigid beta-strand mimetic to provide hydrogen bonding functionality that can act as a template for beta-sheet formation in adjacent peptide strands. The third employs hydrophobic interactions between nearly aromatic groups to buttress hydrogen bonds between beta-strands in aqueous solution. The three strategies will be tested by the synthesis and spectroscopic study of small model compounds. These strategies will be used in conjunction to create parallel and antiparallel beta-sheets containing several peptide strands. Finally, the strategies will be applied to the creation of molecular receptors that use beta-sheet motifs to bind peptides and a catalyst to enantioselectively cleave peptides. The primary health significance of this research is in the development of general strategies for the creation of peptide structure, rather than the development of specific pharmacologically active compounds. In addition, biologically relevant targets have been chosen for study. A soluble version of beta-sheet forming peptide involved in the formation of amyloid plaques will be prepared and characterized. This particular peptide is associated with type II diabetes; related peptides are involved in Alzheimer's disease and scrapie. Enantioselective receptors for D-Ala-D-Ala, the terminus of nascent peptidoglycan, will be prepared, and catalysts to enantioselectively cleave peptides with D-residues at the C-terminus will be developed. These compounds may exhibit antibiotic activity.