Flexibility versus Rigidity for Orally Bioavailable Cyclic Hexapeptides.
Cyclic peptides and macrocycles have the potential to be membrane permeable and orally bioavailable, despite often not complying with the "rule of five" used in medicinal chemistry to guide the discovery of oral drugs. Here we compare solvent-dependent three-dimensional structures of three cyclic hexapeptides containing d-amino acids, prolines, and intramolecular hydrogen bonds. Conformational rigidity rather than flexibility resulted in higher membrane permeability, metabolic stability and oral bioavailability, consistent with less polar surface exposure to solvent and a reduced entropy penalty for transition between polar and nonpolar environments.
Division of Chemistry and Structural Biology, University of Queensland, Brisbane, QLD, 4072, Australia.
Daniel S
DS
Nielsen
Division of Chemistry and Structural Biology, University of Queensland, Brisbane, QLD, 4072, Australia.
Rink-Jan
RJ
Lohman
Division of Chemistry and Structural Biology, University of Queensland, Brisbane, QLD, 4072, Australia.
Huy N
HN
Hoang
Division of Chemistry and Structural Biology, University of Queensland, Brisbane, QLD, 4072, Australia.
Timothy A
TA
Hill
Division of Chemistry and Structural Biology, University of Queensland, Brisbane, QLD, 4072, Australia.
Alun
A
Jones
Division of Chemistry and Structural Biology, University of Queensland, Brisbane, QLD, 4072, Australia.
Andrew J
AJ
Lucke
Division of Chemistry and Structural Biology, University of Queensland, Brisbane, QLD, 4072, Australia. d.fairlie@imb.uq.edu.au.
David P
DP
Fairlie
D000284:Administration, Oral; D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D002942:Circular Dichroism; D019277:Entropy; D006207:Half-Life; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver; D008958:Models, Molecular; D000069463:Olive Oil / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D010539:Permeability; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D012997:Solvents / Q000737:chemistry
D000596:Amino Acids; D000069463:Olive Oil; D010456:Peptides, Cyclic; D012997:Solvents
NMR spectroscopy; cyclic peptides; oral bioavailability; peptides; permeability