The thrust of this continuing program is to develop and apply principles of structure-based design in devising molecules that mimic peptides and proteins. These goals encompass both the control of peptide conformation, with small oligomers imitating important domains of larger proteins, as well as the design of non-peptidic structures that can compete with peptides in binding to macromolecular receptors. Five projects are outlined: 1) Host molecules that are capable of complexing peptide guests through a beta-sheet motif will be developed as chemical antibodies ; self-complementary hosts will be able to dimerize and provide stabilized segments of four-stranded beta-sheets. 2) The 5- aza-3-amino-2-cyclohexenone unit will be explored as a beta-sheet- stabilizing moiety in the context of peptide-co-oligomers. These units will be used a) to induce self-assembly of these co-oligomers, b) to enhance the complexing ability of the peptide hosts in part 1), and c) as the key feature in molecules that may be able to block the formation of amyloid beta-sheets. 3) Molecules that induce the alpha-helical conformation when appended to the termini of an oligopeptide will be explored further. Synthesis of a C-terminal template will be completed, and this and the N-terminal template developed during the previous grant period will be used to make mimics of the CMV protease dimerization helix and the p53 tumor suppressor transactivation domain. 4) A general process developed in the preceding grant period for identification of macrocyclic peptidase inhibitors will be elaborated. The approach will be used to make analogs of the trypsin inhibitor A90720A, and will also be generalized to novel ring systems, transition state analogs, and other peptidase classes. 5) The chemistry of peptide-ketals will be explored as a route to novel structures which may serve as beta-turn mimetics and which are readily assembled in a combinatorial fashion. The results from these studies will afford molecules with novel activity whose behavior will provide insight into biological structure and function.
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