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.

A series of hydrophobically-modified analogues of the peptide cyclo-[dPAKKR] were prepared and examined for their neurotropic activity, stability in plasma, and membrane permeability.Figure optionsDownload as PowerPoint slide