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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease*
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Magnetic Resonance Spectroscopy
  • Protein Binding
  • Protein Structure, Secondary
  • Sulindac / analogs & derivatives*
  • Sulindac / chemistry
  • Sulindac / therapeutic use


  • Amyloid beta-Peptides
  • Anti-Inflammatory Agents, Non-Steroidal
  • Sulindac
  • sulindac sulfide

Associated data

  • PDB/2LMN
  • PDB/2LMP