J Alzheimers Dis. 2018;64(3):859-873. doi: 10.3233/JAD-180165.
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.
可扩散的淀粉样蛋白-β（Aβ）寡聚体目前被认为是最具细胞毒性的 Aβ 聚集物，并被认为是引发阿尔茨海默病（AD）发病机制的原因。因此，Aβ 寡聚体是 AD 药物开发的一个突出靶点。此前，我们报道了我们唯一的 D-对映体 D3 及其衍生物作为 AD 药物候选物。在这里，我们将最有前途的 D3 衍生物之一 ANK6 与其串联版本（tANK6）及其头对头环化异构体（cANK6r）进行比较。体外试验研究了 D-肽抑制 Aβ 聚集、消除 Aβ 寡聚体和降低 Aβ 诱导的细胞毒性的能力，结果表明这三种 D-肽都能有效地靶向 Aβ。随后在野生型小鼠中进行的三种全 D-肽的临床前药代动力学研究表明，cANK6r 具有有希望的血脑屏障通透性，在大脑中产生最高水平。这些肽降低 Aβ 毒性的能力及其显著的脑/血浆比使它们成为有前途的 AD 药物候选物。
