期刊
CHEMPLUSCHEM
卷 86, 期 6, 页码 840-851出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cplu.202000814
关键词
α β oligomerization inhibitors; amyloids; foldamers; peptidomimetics; peptidotriazolamers
资金
- BMBF-funded de.NBI Cloud within the German Network for Bioinformatics Infrastructure (de.NBI) [031A537B, 031A533A, 031A538A, 031A533B, 031A535A, 031A537C, 031A534A, 031A532B]
- Projekt DEAL
Peptidotriazolamers can act as modulators of Aβ(1-42) oligomerization, with some active peptidotriazolamers able to interfere with the formation of toxic early Aβ oligomers and even cross the blood-brain barrier, demonstrating potential for drug development applications.
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 beta (A beta) 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 (KLVFF20)-L-16 and G(39)VVIA(42) in A beta(1-42). We found that peptidotriazolamers act as modulators of the A beta(1-42) oligomerization. Some peptidotriazolamers are able to interfere with the formation of toxic early A beta 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.
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