title: Structural Mechanism of the Interaction of Alzheimer Disease Aβ Fibrils with the Non-steroidal Anti-inflammatory Drug (NSAID) Sulindac Sulfide.
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.
authors.affiliation: From the Munich Center for Integrated Protein Science at Department Chemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Prade
authors.affiliation: Molecular Modeling, Institute of Medical Physics and Biophysics, Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Heiko J
authors.initials: HJ
authors.lastname: Bittner
authors.affiliation: From the Munich Center for Integrated Protein Science at Department Chemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany.
authors.forename: Riddhiman
authors.initials: R
authors.lastname: Sarkar
authors.affiliation: CIC Energigune, Albert Einstein 48, 01510 Miñano, Álava, Spain.
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Lopez Del Amo
authors.affiliation: Bruker BioSpin, Silberstreifen 4, 76287 Rheinstetten, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Althoff-Ospelt
authors.affiliation: the Department of Pharmacology and Therapeutics, McGill University, Montreal Quebec H3G 1Y6, Canada, and.
authors.forename: Gerd
authors.initials: G
authors.lastname: Multhaup
authors.affiliation: Molecular Modeling, Institute of Medical Physics and Biophysics, Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hildebrand
authors.affiliation: 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.
authors.forename: Bernd
authors.initials: B
authors.lastname: Reif
mesh_terms: D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013467:Sulindac / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D013467:Sulindac; C025462:sulindac sulfide
keywords: Alzheimer disease; amyloid; drug design; ligand interactions; magic angle spinning; protein structure; solid-state NMR