This proposal describes an approach to facilitate the discovery of peptide based receptor agonists/antagonists or enzyme inhibitors. In this approach, receptors and enzymes are used as affinity reagents to select tightly binding peptides from equimolar mixtures of synthetic peptides. We have already developed methods for the controlled synthesis of peptide mixtures. The structures of these bound peptides will be determined by a combination of analytical techniques. A model system, consisting of a monoclonal antibody of known specificity, will be used to test the feasibility of this "biochemical selection" approach. An affinity column with the antibody will be used to select tightly binding peptides from an equimolar mixture of peptides and the bound peptide or peptides will be characterized. Our long term goal is to develop generic methods which will allow the rapid discovery of peptides which bind tightly to protein receptors, enzymes or antibodies. These tightly binding peptides will then serve as lead compounds for the development of new therapeutic agents
