Alpha 2.0
Login Register
» Articles » PMID: 8956330

The Effect of Conformation on Membrane Permeability of an Acyloxyalkoxy-linked Cyclic Prodrug of a Model Hexapeptide

Overview
Journal Pharm Res
Specialties Pharmacology
Pharmacy
Date 1996 Nov 1
PMID 8956330
Citations 15
Authors
S Gangwar
S D Jois
T J Siahaan
D G Vander Velde
V J Stella
R T Borchardt
Affiliations
Soon will be listed here.
Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Citing Articles

Structure of a Cyclic Peptide as an Inhibitor of Transcription: NMR and Molecular Dynamics Simulations.

Stephanie F, Tambunan U, Kuczera K, Siahaan T Pharmaceuticals (Basel). 2024; 17(11).

PMID: 39598454 PMC: 11597662. DOI: 10.3390/ph17111545.

Lessons for Oral Bioavailability: How Conformationally Flexible Cyclic Peptides Enter and Cross Lipid Membranes.

Linker S, Schellhaas C, Kamenik A, Veldhuizen M, Waibl F, Roth H J Med Chem. 2023; 66(4):2773-2788.

PMID: 36762908 PMC: 9969412. DOI: 10.1021/acs.jmedchem.2c01837.

Polar/apolar interfaces modulate the conformational behavior of cyclic peptides with impact on their passive membrane permeability.

Linker S, Schellhaas C, Ries B, Roth H, Fouche M, Rodde S RSC Adv. 2022; 12(10):5782-5796.

PMID: 35424539 PMC: 8981571. DOI: 10.1039/d1ra09025a.

Pathways and progress in improving drug delivery through the intestinal mucosa and blood-brain barriers.

Laksitorini M, Prasasty V, Kiptoo P, Siahaan T Ther Deliv. 2014; 5(10):1143-63.

PMID: 25418271 PMC: 4445828. DOI: 10.4155/tde.14.67.

Modeling kinetics of subcellular disposition of chemicals.

Balaz S Chem Rev. 2009; 109(5):1793-899.

PMID: 19265398 PMC: 2682929. DOI: 10.1021/cr030440j.

References
1.
Cefalu W, Pardridge W . Restrictive transport of a lipid-soluble peptide (cyclosporin) through the blood-brain barrier. J Neurochem. 1985; 45(6):1954-6. DOI: 10.1111/j.1471-4159.1985.tb10557.x. View
2.
Ramachandran G, Mitra A . An explanation for the rare occurrence of cis peptide units in proteins and polypeptides. J Mol Biol. 1976; 107(1):85-92. DOI: 10.1016/s0022-2836(76)80019-8. View
3.
Conradi R, Hilgers A, Ho N, Burton P . The influence of peptide structure on transport across Caco-2 cells. II. Peptide bond modification which results in improved permeability. Pharm Res. 1992; 9(3):435-9. DOI: 10.1023/a:1015867608405. View
4.
Rose G, Gierasch L, Smith J . Turns in peptides and proteins. Adv Protein Chem. 1985; 37:1-109. DOI: 10.1016/s0065-3233(08)60063-7. View
5.
Perczel A, Fasman G . Quantitative analysis of cyclic beta-turn models. Protein Sci. 1992; 1(3):378-95. PMC: 2142200. DOI: 10.1002/pro.5560010310. View