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Combined experimental and simulation studies suggest a revised mode of action of the anti-Alzheimer disease drug NQ-Trp.

Chemistry (Weinheim an der Bergstrasse, Germany) (2015-07-17)
Olivia Berthoumieu, Phuong H Nguyen, Maria P Del Castillo-Frias, Sabrina Ferre, Bogdan Tarus, Jessica Nasica-Labouze, Sabrina Noël, Olivier Saurel, Claire Rampon, Andrew J Doig, Philippe Derreumaux, Peter Faller
ABSTRACT

Inhibition of the aggregation of the monomeric peptide β-amyloid (Aβ) into oligomers is a widely studied therapeutic approach in Alzheimer's disease (AD). Many small molecules have been reported to work in this way, including 1,4-naphthoquinon-2-yl-L-tryptophan (NQ-Trp). NQ-Trp has been reported to inhibit aggregation, to rescue cells from Aβ toxicity, and showed complete phenotypic recovery in an in vivo AD model. In this work we investigated its molecular mechanism by using a combined approach of experimental and theoretical studies, and obtained converging results. NQ-Trp is a relatively weak inhibitor and the fluorescence data obtained by employing the fluorophore widely used to monitor aggregation into fibrils can be misinterpreted due to the inner filter effect. Simulations and NMR experiments showed that NQ-Trp has no specific "binding site"-type interaction with mono- and dimeric Aβ, which could explain its low inhibitory efficiency. This suggests that the reported anti-AD activity of NQ-Trp-type molecules in in vivo models has to involve another mechanism. This study has revealed the potential pitfalls in the development of aggregation inhibitors for amyloidogenic peptides, which are of general interest for all the molecules studied in the context of inhibiting the formation of toxic aggregates.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sodium hydroxide solution, 1.0 N, BioReagent, suitable for cell culture
Sigma-Aldrich
DL-Tryptophan, ≥99% (HPLC)
Sigma-Aldrich
DL-Tryptophan, ≥99% (HPLC)
Sigma-Aldrich
3-Ethyl-2,4-pentanedione, mixture of tautomers, 98%
Sigma-Aldrich
Sodium hydroxide, BioUltra, for luminescence, ≥98.0% (T), pellets
Sigma-Aldrich
Sodium hydroxide solution, BioUltra, for molecular biology, 10 M in H2O
Sigma-Aldrich
DL-Tryptophan, Vetec, reagent grade, 98%
Sigma-Aldrich
Sodium hydroxide, ultra dry, powder or crystals, 99.99% trace metals basis
Sigma-Aldrich
1,4-Naphthoquinone, 97%
Sigma-Aldrich
NQTrp, ≥98% (HPLC)
Sigma-Aldrich
Sodium hydroxide-16O solution, 20 wt. % in H216O, 99.9 atom % 16O