In Vitro Potency and Preclinical Pharmacokinetic Comparison of All-D-Enantiomeric Peptides Developed for the Treatment of Alzheimer’s Disease
| Autor: | Schartmann, Elena, Schemmert, Sarah, Niemietz, Nicole, Honold, Dominik, Ziehm, Tamar, Tusche, Markus, Elfgen, Anne, Gering, Ian, Brener, Oleksandr, Shah, Nadim Joni, Langen, Karl-Josef, Kutzsche, Janine, Willbold, Dieter, Willuweit, Antje |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
pharmacokinetic profile
Male Amyloid beta-Peptides Dose-Response Relationship Drug Stereoisomerism amyloid-β In Vitro Techniques Tritium PC12 Cells D-enantiomeric peptides Peptide Fragments Rats Mice Inbred C57BL Mice Protein Aggregates Animals Humans Protein Isoforms Tissue Distribution ddc:610 Alzheimer’s disease Oligopeptides Research Article Protein Binding |
| Zdroj: | Journal of Alzheimer's disease 64(3), 859-873 (2018). doi:10.3233/JAD-180165 Journal of Alzheimer's Disease |
| DOI: | 10.3233/JAD-180165 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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