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

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).