Dr. Kahn is a new investigator under the Presidential Young Investigator program. Under this will be studied conformationally restricted mimetics that should provide novel methods of studying the relationship between peptide structure and function. Beyond these fundamental investigations, the industrial applications of this research could prove profound. The ability to mimic the activity of peptides and proteins with synthetic models should prove invaluable in the design of new pharmaceutical agents, enzyme inhibitors, and synthetic catalysts. The investigations are focused on the design and synthesis of systems which mimic peptide beta-turns. The surface localization of turns in proteins and the predominance of potentially reactive functional groups in their side chains has led to the suggestion, which is now partially established, that turns can function as recognition sites which trigger complex immunologic, metabolic, genomic and endocrinologic events. Additionally turns have been implicated as sites of nucleation of protein folding as well as markers for proteolytic degradation and antibody recognition. Evidence obtained by the comparison of the endogenous opioid peptides and the opiate analgesics suggests that the pharmacophoric interactions responsible for the biological activity of these peptides, occur between the side chain alpha substituents and their target receptors. Based on this assessment, with the aid of computer assisted molecular modeling, a nine-membered ring carbocyclic framework has been designed as an idealized mimetic of the pseudocyclic ten-membered ring of a beta-turn. Synthetic strategies which allow for the placement of any of the amino acid side chain functional groups at position R1 through R4 in addition to the introduction of both the amino and carboxy termini are under investigation.
