Design, Structure-Activity, and Molecular Modeling Studies of Potent Renin Inhibitory Peptides Having N-Terminal Nin-For-Trp (Ftr): Angiotensinogen Congeners Modified by P1-P1' Phe-Phe, Sta, LeuΨVal or LeuΨVal Substitutions

Article abstract of DOI:10.1021/jm00396a006

A structure-conformation-activity investigation of several angiotensinogen (ANG) based inhibitors of human renin modified by either Phe-Phe, Sta, LeuΨVal, or LeuΨVal at the P₁-P₁' cleavage site and P₅ Trp(Nⁱⁿ-For) (Ftr) was performed.Specifically, Ac-Ftr-Pro-Phe-His-Phe-Phe-Val-Ftr-NH2 (1) provided a potent (K_I = 2.7 x 10^-8 M) P₁-P₁' Phe-Phe substituted renin inhibitor to initiate these studies.Substitution of the P₁-P₁' Phe-Phe in compound 1 by Sta effected a 1000-fold increase in biological potency for the resultant octapeptide Ac-Ftr-Pro-Phe-His-Sta-Val-Ftr-NH2 (10; K_I = 6.7 x 10^-11 M).Kinetic analysis of compound 10 showed it to be a competitive inhibitor of human renin catalyzed proteolysis of human ANG.Chemical modifications of the compounds 1 and 10 were evaluated on the basis of comparative human plasma renin inhibitory activities (IC 50 values) in vitro.Carboxy-terminal truncation studies on compound 10 showed that the P₂' Val and P₃' Ftr residues could both be eliminated without significant loss (ca. 10-fold) in renin inhibitory activity as exemplified by the pentapeptide Ac-Ftr-Pro-Phe-His-Sta-NH2 (12; IC 50 = 3.8 x 10^-9 M).In addition, the corresponding P₁-P₁' LeuψVal and LeuψVal derivatives of compound 12 were potent renin inhibitors: Ac-Ftr-Pro-Phe-His-LeuψVal-NH2 (13; IC 50 = 3.1 x 10^-10 M) and Ac-Ftr-Pro-Phe-His-LeuψVal-NH2 (14; IC 50 = 2.1 x 10^-8 M).The structure-conformation-activity properties of the N-terminal Ftr substitution of these human renin inhibitors was examined by (1) comparative analysis of several analogues of 1 and Ac-Ftr-Pro-Phe-His-Sta-Ile-NH2 (17; IC 50 = 1.0 x 10^-10 M) having P₅ site modifications by Trp, His, D-Ftr and D-His, (2) deletion of the N-terminal Ftr residue from compound 12 and 17, to provide Ac-Pro-Phe-His-Sta-Ile-NH2 (16; IC 50 = 3.1 x 10^-8 M) and Ac-Pro-Phe-His-Sta-NH2 (15; IC 50 = 5.6 x 10^-6 M), and (3) computer modeling and dynamic studies of compounds 1 and 17 bound to CKH-RENIN, a simulated human renin model, which were focused on identifying potentional intermolecular interactions of their common P₅-P₂ sequence, Ac-Ftr-Pro-Phe-His, at the enzyme active site.Finally, the human renin specificity of selected congeners of compound 10 were determined by comparison to porcine kidney renin in vitro.