The effect of conformation on membrane permeability of an acyloxyalkoxy-linked cyclic prodrug of a model hexapeptide.
OBJECTIVE
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.
Gangwar
S
S
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence 66047, USA.
Jois
S D
SD
Siahaan
T J
TJ
Vander Velde
D G
DG
Stella
V J
VJ
Borchardt
R T
RT
D002463:Cell Membrane Permeability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002942:Circular Dichroism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012995:Solubility; D013329:Structure-Activity Relationship
D010456:Peptides, Cyclic; D011355:Prodrugs