Combined Experimental and Simulation Studies Suggest a Revised Mode of Action of the Anti-Alzheimer Disease Drug NQ-Trp

被引:17
作者
Berthoumieu, Olivia [1 ,2 ]
Nguyen, Phuong H. [3 ]
del Castillo-Frias, Maria P. [4 ]
Ferre, Sabrina [1 ,2 ]
Tarus, Bogdan [3 ]
Nasica-Labouze, Jessica [3 ]
Noel, Sabrina [1 ,2 ]
Saurel, Olivier [5 ,6 ]
Rampon, Claire [7 ]
Doig, Andrew J. [4 ]
Derreumaux, Philippe [3 ,8 ]
Faller, Peter [1 ,2 ]
机构
[1] CNRS, LCC Lab Chim Coordinat, F-31077 Toulouse 4, France
[2] Univ Toulouse, INPT, UPS, F-31077 Toulouse 4, France
[3] Univ Paris Diderot, CNRS, Lab Biochim Theor, Sorbonne Paris Cite,IBPC,UPR 9080, F-75005 Paris, France
[4] Univ Manchester, Fac Life Sci, Manchester Inst Biotechnol, Manchester M1 7DN, Lancs, England
[5] Univ Toulouse, UPS, IPBS Inst Pharmacol & Struct Biol, F-31077 Toulouse, France
[6] CNRS, IPBS, UMR 5089, F-31077 Toulouse, France
[7] Univ Toulouse, CNRS, Ctr Rech Cognit Anim, UPS, F-31062 Toulouse 4, France
[8] Inst Univ France IUF, F-75005 Paris, France
关键词
aggregation; inhibitors; molecular dynamics; peptides; reaction mechanisms; AMYLOID-BETA PEPTIDE; MOLECULAR-MECHANISM; PROTEIN; AGGREGATION; INHIBITION; COMPLEXES; DYNAMICS; BINDING;
D O I
10.1002/chem.201500888
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Inhibition of the aggregation of the monomeric peptide -amyloid (A) 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 A 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 A, 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.
引用
收藏
页码:12657 / 12666
页数:10
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