Structure-conformation relationships of synthetic peptide inhibitors of human renin studied by resonance energy transfer and molecular modeling.
The structure-conformation relationships of a series of angiotensinogen6-13 (ANG6-13, His-Pro-Phe-His-Leu-Val-Ile-His) congeners substituted by Nin-For-Trp (Ftr), D-Ftr or Trp at the N-terminus, Tyr at the C-terminus and Phe psi[CH2NH]Phe at the P1-P'1 cleavage site (i.e. Leu10-Val11) were studied using resonance energy transfer coupled with molecular modeling of the peptide conformation using macromolecular energy refinement and dynamics simulation. Average end-to-end intramolecular distances (r) of the peptides in solution were determined by fluorescence spectroscopy. For example, Ac-Ftr-Pro-Phe-His-Phe psi[CH2NH]Phe-Val-Tyr-NH2 (U-70714E) gave an average intramolecular donor (Tyr)-acceptor (Ftr) distance of 16.3A in aqueous solution. This experimental value was consistent with a distance of 17.9 A determined by molecular modeling of U-70714E to a human renin 3-D structure (developed from known homologous aspartyl protease inhibitor X-ray crystallographic data) followed by simulation of the solution phase conformation of the peptide. An extended backbone secondary structure of U-70714E is suggested from these studies and the relationship(s) of structure-conformation to structure-activity was explored by analysis of several congeners of U-70714E, a potent (IC50 = 3.0 X 10(-9)M) inhibitor of human renin in vitro.
Epps
D E
DE
Physical and Analytical Chemistry, Upjohn Company, Kalamazoo, Michigan.
Mao
B
B
Staples
D J
DJ
Sawyer
T K
TK
D000808:Angiotensinogen / Q000494:pharmacology; D004735:Energy Transfer; D006801:Humans; D008958:Models, Molecular; D009842:Oligopeptides / Q000494:pharmacology; D010436:Pepstatins / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D011487:Protein Conformation; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000808:Angiotensinogen; D009842:Oligopeptides; D010436:Pepstatins; D010446:Peptide Fragments; D010455:Peptides; D000092502:Renin Inhibitors; C014195:Streptomyces pepsin inhibitor; C055797:U 70714E; C055796:angiotensinogen (6-13); C031375:pepstatin