Competitive inhibitors of renin. Inhibitors effective at physiological pH.
Previously we reported the development of competitive inhibitors of renin effective at pH 5.5 (Poulsen, K., Burton, J., and Haber, E. (1973), Biochemistry 12, 3877). At physiologic pH (7.5), the inhibitory constants (Ki) increased and solubility decreased to the point that inhibition could not be demonstrated with these peptides. Modification of the octapeptide sequence, His-Pro-Phe-His-Leu-Leu-Val-Tyr, either by addition of serinol to the carboxyl terminus or by replacement of valine-7 with an isosteric threonyl residue failed to yield peptides active at pH 7.5. Attachment of polyproline sequences to the amino terminus increased solubility from threefold to tenfold and decreased Ki so that competitive inhibition was demonstrable at physiologic pH. In addition, if leucine-6 was replaced in these peptides with a phenylalanyl or tyrosyl residue, Ki decreased (3-12 muM) to give effective competitive inhibitors at physiologic pH in both buffer and in plasma.
D001665:Binding Sites; D001667:Binding, Competitive; D002850:Chromatography, Gel; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D009842:Oligopeptides; D000092502:Renin Inhibitors