The objective of the proposed research is the design, synthesis, and biological evaluation of novel epoxy-polypeptides as potential inactivators of renin and pro-renin. The approach which will be taken to accomplish this objective will be to place an epoxide moiety in a position which approximates the Leu-Leu bond of the Leu-Leu-Val-Tyr sequence of angiotensinogen. It is proposed that the epoxide moiety will simulate the Leu-Leu peptide bond such that the aspartyl carboxyl group in renin's active site which normally attacks the carbonyl carbon of the Leu-Leu peptide bond will attack the epoxide ring of the epoxy-polypeptides after they have become bound to the enzyme. The synthesis of the epoxy-polypeptides will require the synthesis of the novel epoxy amino acid, 2,5-disubstituted-5-amino-3,4-epoxypentanoic acid. This will be accomplished through the development of an asymmetric synthesis of a chiral Wittig reagent. The ability of the epoxy-polypeptides to inactivate both renin and pro-renin will be determined by measuring the percentage of renin activity which remains after the enzyme has been incubated with varying concentrations of epoxy-polypeptide for varying periods of time. Renin activity will be assayed by measuring the angiotensin I generated from hog-renin substrate. Angiotensin I will be measured by radioimmunoassay. The ability of the epoxy-polypeptides to inactivate pepsin and cathepsin D will also be determined so that the specificity of the inactivators can be established.