The synthesis of inhibitors of endothiapepsin

Fryer, Susan Elizabeth (1991) The synthesis of inhibitors of endothiapepsin. University of Southampton, Doctoral Thesis.

Abstract

Potential inhibitors of the microbial aspartic proteinase, endothiapepsin, have been synthesized in order to probe the effect of introducing additional interactions between the inhibitor and the catalytically essential aspartate pair at the active site. The synthesis of a series of five pentapeptides based on the peptide sequence BocAlaAlaXaaArgLeuOH, where Xaa represents an un-natural amino acid, is described. The novel compound (3R/S,4S)-3,4-diamino-3,6-dimethylheptanoic acid, [(3R/S,4S)-methyl-aminostatine] has been synthesized and incorporated into this peptide sequence by classical solution phase methodology. (3S,4S)-3,4-Diamino-6-methylheptanoic acid, [(3S,4S)-aminostatine] and (3R,4S-3,4-diamino-6-methylheptanoic acid, [(3R,4S)-aminostatine] were also synthesized and incorporated into the pentapeptide sequence along with (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, [3S,4S)-statine] and (3R,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, [(3R,4S)-statine]. The inhibitory potencies of these compounds were tested against endothiapepsin and it was found that the (3S,4S) diastereomers of statine and aminostatine were more potent than the corresponding (3R,4S) diastereomers. The methylamino-statine containing peptide displayed activity, but was not as potent as either the statine or aminostatine compounds. A comparison of our results with studies carried out elsewhere, on pepsin and renin, indicates that endothiapepsin exhibits intermediate affinity for the aminostatine compounds. Possible explanations for this are discussed in terms of variations in the nature of the active site of these enzymes and the implications of these differences on enzyme-inhibitor interaction.

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