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J Biol Chem. 2015 Nov 27;290(48):28737-45. doi: 10.1074/jbc.M115.675215. Epub 2015 Sep 28.

Structural Mechanism of the Interaction of Alzheimer Disease Aβ Fibrils with the Non-steroidal Anti-inflammatory Drug (NSAID) Sulindac Sulfide.

Author information

1
From the Munich Center for Integrated Protein Science at Department Chemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany.
2
Molecular Modeling, Institute of Medical Physics and Biophysics, Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
3
CIC Energigune, Albert Einstein 48, 01510 Miñano, Álava, Spain.
4
Bruker BioSpin, Silberstreifen 4, 76287 Rheinstetten, Germany.
5
the Department of Pharmacology and Therapeutics, McGill University, Montreal Quebec H3G 1Y6, Canada, and.
6
From the Munich Center for Integrated Protein Science at Department Chemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany, the Helmholtz-Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Ingolstädter Landtstr. 1, 85764 Neuherberg, Germany reif@tum.de.

Abstract

Alzheimer disease is the most severe neurodegenerative disease worldwide. In the past years, a plethora of small molecules interfering with amyloid-β (Aβ) aggregation has been reported. However, their mode of interaction with amyloid fibers is not understood. Non-steroidal anti-inflammatory drugs (NSAIDs) are known γ-secretase modulators; they influence Aβ populations. It has been suggested that NSAIDs are pleiotrophic and can interact with more than one pathomechanism. Here we present a magic angle spinning solid-state NMR study demonstrating that the NSAID sulindac sulfide interacts specifically with Alzheimer disease Aβ fibrils. We find that sulindac sulfide does not induce drastic architectural changes in the fibrillar structure but intercalates between the two β-strands of the amyloid fibril and binds to hydrophobic cavities, which are found consistently in all analyzed structures. The characteristic Asp(23)-Lys(28) salt bridge is not affected upon interacting with sulindac sulfide. The primary binding site is located in the vicinity of residue Gly(33), a residue involved in Met(35) oxidation. The results presented here will assist the search for pharmacologically active molecules that can potentially be employed as lead structures to guide the design of small molecules for the treatment of Alzheimer disease.

KEYWORDS:

Alzheimer disease; amyloid; drug design; ligand interactions; magic angle spinning; protein structure; solid-state NMR

PMID:
26416887
PMCID:
PMC4661391
DOI:
10.1074/jbc.M115.675215
[Indexed for MEDLINE]
Free PMC Article

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