Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers

J Am Chem Soc. 2006 Mar 1;128(8):2510-1. doi: 10.1021/ja0563455.

Abstract

Little is known about the effect of conformation on passive membrane diffusion rates in small molecules. Evidence suggests that intramolecular hydrogen bonding may play a role by reducing the energetic cost of desolvating hydrogen bond donors, especially amide N-H groups. We set out to test this hypothesis by investigating the passive membrane diffusion characteristics of a series of cyclic peptide diastereomers based on the sequence cyclo[Leu-Leu-Leu-Leu-Pro-Tyr]. We identified two cyclic hexapeptide diastereomers based on this sequence, whose membrane diffusion rates differed by nearly two log units. Results of solution NMR studies and hydrogen/deuterium (H/D) exchange experiments showed that membrane diffusion rates correlated with the degree of intramolecular hydrogen bonding and H/D exchange rates. The most permeable diastereomer, cyclo[d-Leu-d-Leu-Leu-d-Leu-Pro-Tyr] (1), exhibited a passive membrane diffusion rate comparable to that of the orally available drug cyclosporine A.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Membrane Permeability
  • Hydrogen Bonding
  • Lipid Bilayers / chemistry
  • Lipid Bilayers / metabolism
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular / methods
  • Oligopeptides / chemistry*
  • Oligopeptides / metabolism
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / metabolism
  • Proline / chemistry
  • Proline / metabolism
  • Protein Conformation
  • Stereoisomerism

Substances

  • Lipid Bilayers
  • Oligopeptides
  • Peptides, Cyclic
  • Proline