title: Combined experimental and simulation studies suggest a revised mode of action of the anti-Alzheimer disease drug NQ-Trp.
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.
authors.affiliation: CNRS, LCC (Laboratoire de Chimie de Coordination), 205 route de Narbonne, BP 44099, 31077 Toulouse Cedex 4 (France) and Université de Toulouse, UPS, INPT, 31077 Toulouse Cedex 4 (France).
authors.forename: Olivia
authors.initials: O
authors.lastname: Berthoumieu
authors.affiliation: Laboratoire de Biochimie Théorique, UPR 9080 CNRS, Université Paris Diderot, Sorbonne Paris Cité, IBPC, 13 rue Pierre et Marie Curie, 75005 Paris (France).
authors.forename: Phuong H
authors.initials: PH
authors.lastname: Nguyen
authors.affiliation: Manchester Institute of Biotechnology, Faculty of Life Sciences, The University of Manchester, 131 Princess Street, Manchester M1 7DN (UK).
authors.forename: Maria P Del
authors.initials: MP
authors.lastname: Castillo-Frias
authors.affiliation: CNRS, LCC (Laboratoire de Chimie de Coordination), 205 route de Narbonne, BP 44099, 31077 Toulouse Cedex 4 (France) and Université de Toulouse, UPS, INPT, 31077 Toulouse Cedex 4 (France).
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ferre
authors.affiliation: Laboratoire de Biochimie Théorique, UPR 9080 CNRS, Université Paris Diderot, Sorbonne Paris Cité, IBPC, 13 rue Pierre et Marie Curie, 75005 Paris (France).
authors.forename: Bogdan
authors.initials: B
authors.lastname: Tarus
authors.affiliation: Laboratoire de Biochimie Théorique, UPR 9080 CNRS, Université Paris Diderot, Sorbonne Paris Cité, IBPC, 13 rue Pierre et Marie Curie, 75005 Paris (France).
authors.forename: Jessica
authors.initials: J
authors.lastname: Nasica-Labouze
authors.affiliation: CNRS, LCC (Laboratoire de Chimie de Coordination), 205 route de Narbonne, BP 44099, 31077 Toulouse Cedex 4 (France) and Université de Toulouse, UPS, INPT, 31077 Toulouse Cedex 4 (France).
authors.forename: Sabrina
authors.initials: S
authors.lastname: Noël
authors.affiliation: IPBS Institute of Pharmacology and Structural Biology, Université de Toulouse, UPS, 205 route de Narbonne, 31077 Toulouse (France).|IPBS, UMR 5089, CNRS, 205 route de Narbonne, BP 64182, 31077 Toulouse (France).
authors.forename: Olivier
authors.initials: O
authors.lastname: Saurel
authors.affiliation: Université de Toulouse, UPS, CNRS, Centre de Recherches sur la Cognition, Animale, 118 route de Narbonne, 31062 Toulouse Cedex 4 (France).
authors.forename: Claire
authors.initials: C
authors.lastname: Rampon
authors.affiliation: Manchester Institute of Biotechnology, Faculty of Life Sciences, The University of Manchester, 131 Princess Street, Manchester M1 7DN (UK). andrew.doig@manchester.ac.uk.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Doig
authors.affiliation: Laboratoire de Biochimie Théorique, UPR 9080 CNRS, Université Paris Diderot, Sorbonne Paris Cité, IBPC, 13 rue Pierre et Marie Curie, 75005 Paris (France). philippe.derreumaux@ibpc.fr.|Institut Universitaire de France, IUF, 103 Boulevard Saint-Michel, 75005 Paris (France). philippe.derreumaux@ibpc.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Derreumaux
authors.affiliation: CNRS, LCC (Laboratoire de Chimie de Coordination), 205 route de Narbonne, BP 44099, 31077 Toulouse Cedex 4 (France) and Université de Toulouse, UPS, INPT, 31077 Toulouse Cedex 4 (France). faller@lcc-toulouse.fr.
authors.forename: Peter
authors.initials: P
authors.lastname: Faller
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D009285:Naphthoquinones / Q000737:chemistry* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C582984:1,4-naphthoquinon-2-yltryptophan; D016229:Amyloid beta-Peptides; D009285:Naphthoquinones; D010446:Peptide Fragments; D014364:Tryptophan
keywords: aggregation; inhibitors; molecular dynamics; peptides; reaction mechanisms