Peptidotriazolamers Inhibit Aβ(1-42) Oligomerization and Cross a Blood-Brain-Barrier Model

Abstract

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" K¹⁶ LVFF²⁰ and G³⁹ VVIA⁴² 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.

Keywords: amyloids; foldamers; peptidomimetics; peptidotriazolamers; αβ oligomerization inhibitors.