Renin inhibitory peptides. A .beta.-aspartyl residue as a replacement for the histidyl residue at the P-2 site

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Abstract
In an effort to decrease the size and to increase the hydrophilicity of the previously prepared renin inhibitory peptides, it was postulated that one might be able to take advantage of the polar Thr-84 on the flap region of the enzyme renin by potential hydrogen bonding to polar functionality on the inhibitory peptide at the P-2 site. A .beta.-aspartyl residue with a carboxylic acid group was proposed to be a possible replacement for this histidyl residue at the P-2 site. A series of renin inhibitory peptides were prepared with the .beta.-aspartyl residue to probe the structure-activity relationship of the resulting peptides. Potent inhibitory peptides could be realized with activity in the subnanomolar range. Molecular modeling was also undertaken to investigate the interactions between the enzyme active site and the new inhibitors and to suggest a possible mode of binding of these ligands to the enzyme. From this modeling study, the role of Ser-229 at the active site in the bound conformer of the inhibitors was suggested. It was further noted in the analogue study that a malic acid residue, which is the oxygen analogue of the .beta.-aspartic acid residue, could lead to further enhancement of inhibitory potency of congeneric peptides. Small renin inhibitors, such as compound XII with molecular weight 535 and with no .alpha.-amino acid residue, could be prepared and exhibited renin inhibitory activity in the nanomolar range.