Organic and Bioorganic Chemistry, Department of Chemistry Bielefeld University, PO Box, 100131, 33501, Bielefeld, Germany.
BioCIS, CNRS, Université Paris Saclay, 5 rue Jean-Baptiste Clément, 92296, Châtenay-Malabry, France.
Chempluschem. 2021 Jun;86(6):840-851. doi: 10.1002/cplu.202000814. Epub 2021 May 6.
In peptidotriazolamers every second peptide bond is replaced by a 1H-1,2,3-triazole. Such foldamers are expected to bridge the gap in molecular weight between small-molecule drugs and protein-based drugs. Amyloid β (Aβ) aggregates play an important role in Alzheimer's disease. We studied the impact of amide bond replacements by 1,4-disubstituted 1H-1,2,3-triazoles on the inhibitory activity of the aggregation "hot spots" K LVFF and G VVIA in Aβ(1-42). We found that peptidotriazolamers act as modulators of the Aβ(1-42) oligomerization. Some peptidotriazolamers are able to interfere with the formation of toxic early Aβ oligomers, depending on the position of the triazoles, which is also supported by computational studies. Preliminary in vitro results demonstrate that a highly active peptidotriazolamer is also able to cross the blood-brain-barrier.
在肽三唑中，每第二个肽键都被 1H-1,2,3-三唑取代。这种折叠体有望在小分子药物和基于蛋白质的药物之间的分子量差距上发挥作用。淀粉样β（Aβ）聚集体在阿尔茨海默病中起着重要作用。我们研究了酰胺键被 1,4-二取代 1H-1,2,3-三唑取代对 Aβ（1-42）中聚集“热点” KLVFF 和 GV VIA 的抑制活性的影响。我们发现肽三唑作为 Aβ（1-42）寡聚化的调节剂。一些肽三唑能够干扰毒性早期 Aβ 寡聚物的形成，这取决于三唑的位置，这也得到了计算研究的支持。初步的体外结果表明，一种高活性的肽三唑也能够穿过血脑屏障。
