title: 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, Leu psi[CH(OH)CH2]Val or leu psi[CH2NH]Val substitutions.
abstract: A structure-conformation-activity investigation of several angiotensinogen (ANG) based inhibitors of human renin modified by either Phe-Phe, Sta, Leu psi[CH2NH]Val, or Leu psi[CH(OH)CH2]Val at the P1-P1' clevage site and P5 Trp(Nin-For) (Ftr) was performed. Specifically, Ac-Ftr-Pro-Phe-His-Phe-Phe-Val-Ftr-NH2 (1) provided a potent (KI = 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 1,000-fold increase in biological potency for the resultant octapeptide Ac-Ftr-Pro-Phe-His-Sta-Val-Ftr-NH2 (10; KI = 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 (IC50 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; IC50 = 3.8 X 10(-9) M). In addition, the corresponding P1-P1' Leu psi[CH(OH)CH2]Val and Leu psi[CH2NH]Val derivatives of compound 12 were potent renin inhibitors: Ac-Ftr-Pro-Phe-His-Leu psi[CH(OH)CH2]Val-NH2 (13; IC50 = 3.1 X 10(-10) M) and Ac-Ftr-Pro-Phe-His-Leu psi[CH2NH]Val-NH2 (14; IC50 = 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; IC50 = 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 compounds 12 and 17, to provide Ac-Pro-Phe-His-Sta-Ile-NH2 (16; IC50 = 3.1 X 10(-8) M) and Ac-Pro-Phe-His-Sta-NH2 (15; IC50 = 5.6 X 10(-6) M), and (3) computer modeling and dynamics studies of compounds 1 and 17 bound to CKH-RENIN, a simulated human renin model, which were focused on identifying potential intermolecular interactions of their common P5-P2 sequence, Ac-Ftr-Pro-Phe-His, at the enzyme active site.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Biotechnology-Regulatory Peptide Research, Upjohn Company, Kalamazoo, Michigan 49001.
authors.forename: T K
authors.initials: TK
authors.lastname: Sawyer
authors.forename: D T
authors.initials: DT
authors.lastname: Pals
authors.forename: B
authors.initials: B
authors.lastname: Mao
authors.forename: D J
authors.initials: DJ
authors.lastname: Staples
authors.forename: A E
authors.initials: AE
authors.lastname: de Vaux
authors.forename: L L
authors.initials: LL
authors.lastname: Maggiora
authors.forename: J A
authors.initials: JA
authors.lastname: Affholter
authors.forename: W
authors.initials: W
authors.lastname: Kati
authors.forename: D
authors.initials: D
authors.lastname: Duchamp
authors.forename: J B
authors.initials: JB
authors.lastname: Hester
mesh_terms: D000595:Amino Acid Sequence; D000808:Angiotensinogen / Q000138:chemical synthesis*; D006801:Humans; D007202:Indicators and Reagents; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D000808:Angiotensinogen; D007202:Indicators and Reagents; D009842:Oligopeptides; D000092502:Renin Inhibitors