Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers.
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.
Rezai
Taha
T
Department of Chemistry and Biochemistry, University of California, Santa Cruz, 95064, USA.
Yu
Bin
B
Millhauser
Glenn L
GL
Jacobson
Matthew P
MP
Lokey
R Scott
RS
D002463:Cell Membrane Permeability; D006860:Hydrogen Bonding; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism; D011392:Proline / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D013237:Stereoisomerism
D008051:Lipid Bilayers; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011392:Proline