Year-end Sale % OFF 
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.
Highlights
Neurodegenerative diseases caused by the aggregation of misfolded proteins are about to become a threatening risk for our aging society and health care systems
D-peptides’ in vitro potencies The A aggregation assay was performed to compare the potencies of ANK6, tANK6, and cANK6r, with D3’s potency to inhibit the formation of ThTpositive amyloid- protein (A)1-42 fibrils
To find out whether ANK6, tANK6, and cANK6r lowered the cytotoxic effect of A1-42 on the cell viability of PC12 cells, MTT assays were performed with various D-peptide concentrations (Fig. 2)
Summary
Researchers entitle soluble oligomers to be the most neurotoxic A species [2] Both A and tau, with their formation, aggregation, and degradation, are prominent targets in AD drug development [3, 4]. The most promising seven peptides (ANK1-ANK7) were selected and further investigated in vitro awarding ANK6 the most promising properties [23] Another optimization strategy to increase the peptides’ efficiency to eliminate toxic A oligomers as well as to increase pharmacokinetic availability was the head-to-tail cyclization of D3 and various derivatives [24, 25]. Aggregation assay), on A oligomer elimination (QIAD assay), and on A1-42-induced cytotoxicity (cell viability assay) In another pre-in vivo test, the D-peptides’ plasma protein binding affinities were determined. Special attention was paid to the D-peptides’ uptake into the brain and their blood-brain barrier (BBB) permeability
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
