PMID: 8956330Nov 1, 1996Paper

The effect of conformation on membrane permeability of an acyloxyalkoxy-linked cyclic prodrug of a model hexapeptide

Pharmaceutical Research
S GangwarR T Borchardt

Abstract

To determine the different conformations of the acyloxyalkoxy-linked cyclic prodrug 1 of the model hexapeptide 2 in solution and to investigate the relationship between these solution conformations and the cellular permeability characteristics of this prodrug. Two-dimensional Homonuclear Hartmann-Hahn spectroscopy, Rotating-Frame Overhouser effect spectroscopy, circular dichroism and molecular dynamics simulations were used to find the solution conformers of cyclic prodrug 1. Our spectroscopic findings suggest that cyclic prodrug 1 exhibits a major and a minor conformer in solution. The major conformer appears to have a well-defined secondary structure, which involves a beta-turn and 4-->1 intramolecular hydrogen bond, creating a compact structure with a reduced average hydrodynamic radius compared to the model hexapeptide 2. The increased ability of cyclic prodrug 1 to permeate membranes compared to the model hexapeptide 2 could be due to reduction in the average hydrodynamic radius of the molecule facilitating paracellular flux and/or the reduction in the hydrogen bonding potential facilitating transcellular flux.

Citations

Jul 16, 1999·The Journal of Peptide Research : Official Journal of the American Peptide Society·B WangR T Borchardt
Nov 25, 2014·Therapeutic Delivery·Marlyn LaksitoriniTeruna J Siahaan
Jan 27, 2019·Angewandte Chemie·Francesco ColizziModesto Orozco
Mar 13, 2008·Biopolymers·D Gomika Udugamasooriya, Mark R Spaller
Apr 26, 2002·The Journal of Peptide Research : Official Journal of the American Peptide Society·H OuyangT J Siahaan
Jul 16, 1999·The Journal of Peptide Research : Official Journal of the American Peptide Society·O S GudmundssonR T Borchardt
May 20, 2005·The Journal of Pharmacology and Experimental Therapeutics·Philip L LorenziGordon L Amidon
Jul 16, 1999·The Journal of Peptide Research : Official Journal of the American Peptide Society·O S GudmundssonR T Borchardt
Apr 6, 2005·The Journal of Pharmacy and Pharmacology·M Kyle HaddenThomas A Dix
Mar 13, 2014·Chemistry : a European Journal·Andrés Feher-VoelgerTomás Martín
Mar 7, 2009·Chemical Reviews·Stefan Balaz
Apr 4, 2006·Molecular Pharmaceutics·Xiaohong Qi
Nov 21, 2018·Journal of Chemical Information and Modeling·Jagna WitekSereina Riniker

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