Modified low molecular weight cyclic peptides as mimetics of BDNF with improved potency, proteolytic stability and transmembrane passage in vitro.
We recently reported the development of the BDNF mimetic peptide cyclo-[dPAKKR] 1 which promotes the survival of cultured sensory neurons via a trkB independent mechanism [Fletcher, J. M.; Morton, C. M.; Zwar, R. A.; Murray, S. S.; O'Leary, P. D.; Hughes, R. A. J. Biol. Chem.2008, 283, 33375]. In the present study we prepared a series of hydrophobically-modified analogues of 1 with an eye to improving its pharmacokinetic properties. Select members of this second generation of compounds showed improved biological activity, stability in plasma, and an ability to cross model biological membranes.
Fletcher
Jordan M
JM
The Department of Pharmacology, The University of Melbourne, Victoria 3010, Australia.
Hughes
Richard A
RA
D000595:Amino Acid Sequence; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000737:chemistry*; D002463:Cell Membrane Permeability; D002470:Cell Survival; D002478:Cells, Cultured; D002642:Chick Embryo; D004355:Drug Stability; D009474:Neurons / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020813:Receptor, trkB / Q000737:chemistry / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D010456:Peptides, Cyclic; D020813:Receptor, trkB