Structure‐conformation relationships of synthetic peptide inhibitors of human renin studied by resonance energy transfer and molecular modeling

Wiley - Tập 31 Số 1 - Trang 22-34 - 1988
Dennis E. Van Epps1, Boryeu Mao2, D. J. Staples3, Tomi K. Sawyer3
1Physical and Analytical Chemistry, The Upjohn Company, Kalamazoo, Michigan, USA
2Computational Chemistry, The Upjohn Company, Kalamazoo, Michigan, USA
3Biopolymer Chemistry, The Upjohn Company, Kalamazoo, Michigan, USA

Tóm tắt

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 PheΨ[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‐PheΨ[CH2NH]Phe‐Val‐Tyr‐NH2 (U‐70714E) gave an average intramolecular donor (Tyr)‐acceptor (Ftr) distance of 16.3 Å in aqueous solution. This experimental value was consistent with a distance of 17.9 Å 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 × 10−9m) inhibitor of human renin in vitro.

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Wiley

Tập 31 Số 1

22-34

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