In vitro potency and preclinical pharmacokinetic comparison of all-d-enantiomeric peptides developed for the treatment of Alzheimer's disease

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Abstract

Diffusible amyloid-β (Aβ) oligomers are currently presumed to be the most cytotoxic Aβ assembly and held responsible to trigger the pathogenesis of Alzheimer's disease (AD). Thus, Aβ oligomers are a prominent target in AD drug development. Previously, we reported on our solely D-enantiomeric peptide D3 and its derivatives as AD drug candidates. Here, we compare one of the most promising D3 derivatives, ANK6, with its tandem version (tANK6), and its head-to-tail cyclized isoform (cANK6r). In vitro tests investigating the D-peptides' potencies to inhibit Aβ aggregation, eliminate Aβ oligomers, and reduce Aβ-induced cytotoxicity revealed that all three D-peptides efficiently target Aβ. Subsequent preclinical pharmacokinetic studies of the three all-D-peptides in wildtype mice showed promising blood-brain barrier permeability with cANK6r yielding the highest levels in brain. The peptides' potencies to lower Aβ toxicity and their remarkable brain/plasma ratios make them promising AD drug candidates.

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Schartmann, E., Schemmert, S., Niemietz, N., Honold, D., Ziehm, T., Tusche, M., … Willuweit, A. (2018). In vitro potency and preclinical pharmacokinetic comparison of all-d-enantiomeric peptides developed for the treatment of Alzheimer’s disease. Journal of Alzheimer’s Disease, 64(3), 859–873. https://doi.org/10.3233/JAD-180165

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