Synthesis of peptides related to the prosegment of mouse submaxillary gland renin precursor: an approach to renin inhibitors.

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Abstract
The complete sequence of the structural gene coding for mouse submaxillary gland renin was recently reported and the amino acid sequence of preprorenin was reduced. This sequence includes a 45-amino acid peptide that corresponds to the prosegment of the renin precursor. To investigate whether peptides related to the renin prosegment are able to inhibit renin activity, the following 4 peptides were synthesized: Arg-Ile-Pro-OMe, butyloxy-carbonyl(Boc)-Leu-Lys-Lys-Met-Pro-OMe, Boc-Arg-Ile-Pro-Leu-Lys-Lys-Met-Pro-OMe and Boc-Glu-Arg-Ile-Pro-Leu-Lys-Lys-Met-Pro-OMe (corresponding to amino acids 12-14, 15-19, 12-19 and 11-19, respectively, of the renin prosegment). All 4 peptides inhibited the activity of pure mouse submaxillary renin on a porcine synthetic tetradecapeptide in vitro, and the most potent inhibitor exhibited IC50 [median inhibitory concentration] values in the micromolar range. Enzymatic kinetic studies carried out using peptide 15-19 showed an uncompetitive or a mixed type of inhibition with a Ki value of 2.3 .times. 10-6 M at 37.degree. C in 0.5 M citrate/phosphate buffer (pH 6.0).