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

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.Peer reviewe

Development of New Fluorescent PeptideBased Probes for the Specific Recognition of the A beta 42 Oligomer Species

Hericks L, Tonali N, Sewald N. Development of New Fluorescent PeptideBased Probes for the Specific Recognition of the A beta 42 Oligomer Species. In: Journal of Peptide Science . Vol 28. Hoboken: Wiley; 2022

Real-Time BODIPY-Binding Assay To Screen Inhibitors of the Early Oligomerization Process of A beta 1-42 Peptide

Tonali NM, Dodero VI, Kaffy J, Hericks L, Ongeri S, Sewald N. Real-Time BODIPY-Binding Assay To Screen Inhibitors of the Early Oligomerization Process of A beta 1-42 Peptide. ChemBioChem. 2020;21(8):1129-1135.Misfolding and aggregation of amyloid beta 1-42 peptide (A beta 1-42) play a central role in the pathogenesis of Alzheimer's disease (AD). Targeting the highly cytotoxic oligomeric species formed during the early stages of the aggregation process represents a promising therapeutic strategy to reduce the toxicity associated with A beta 1-42. Currently, the thioflavin T (ThT) assay is the only established spectrofluorometric method to screen aggregation inhibitors. The success of the ThT assay is that it can detect A beta 1-42 aggregates with high beta-sheet content, such as protofibrils or fibrils, which appear in the late aggregation steps. Unfortunately, by using the ThT assay, the detection of inhibitors of early soluble oligomers that present a low beta-sheet character is challenging. Herein, a new, facile, and robust boron-dipyrromethene (BODIPY) real-time assay suitable for 96-well plate format, which allows screening of compounds as selective inhibitors of the formation of A beta 1-42 oligomers, is reported. These inhibitors decrease the cellular toxicity of A beta 1-42, although they fail in the ThT assay. The findings have been confirmed and validated by structural analysis and cell viability assays under comparable experimental conditions. It is demonstrated that the BODIPY assay is a convenient method to screen and discover new candidate compounds that slow down or stop the pathological early oligomerization process and are active in the cellular assay. Therefore, it is a suitable complementary screening method of the current ThT assay

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

Tonali NM, Hericks L, Schröder DC, et al. Peptidotriazolamers Inhibit Abeta(1-42) Oligomerization and Cross a Blood-Brain-Barrier Model. ChemPlusChem. 2021;86(6):840-851.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 (Abeta) 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 Abeta(1-42). We found that peptidotriazolamers act as modulators of the Abeta(1-42) oligomerization. Some peptidotriazolamers are able to interfere with the formation of toxic early Abeta 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. © 2021 The Authors. ChemPlusChem published by Wiley-VCH GmbH