Binding of TCA to the prion protein: mechanism, implication for therapy, and application as probe for complex formation of bio-macromolecules

J Biomol Struct Dyn. 2009 Oct;27(2):163-70. doi: 10.1080/07391102.2009.10507306.

Abstract

Tricyclic aromatic compounds (TCA) are promising candidates for treatment of transmissible spongiform encephalopathies. Direct binding to the cellular prion protein (PrP(C)) has been proposed as anti-prion active mechanism. We here show by means of NMR-spectroscopy that binding of TCA occurs with millimolar affinity to motifs consisting of two neighboring aromatic residues (Ar-Ar motif). It is independent of the secondary structure of this motif and of the side chain attached to the TCA and it is not specific to PrP(C). Because biologically inactive 9-aminoacridine (9-aa) binds with similar K(D) as anti-prion active quinacrine, direct interaction with PrP(C) as mechanism of action appears highly unlikely. However, binding of 9-aa to Ar-Ar-motifs in proteins can be used as reporter for biological macromolecule interactions, by measuring changes in T(1)-NMR relaxation times of 9-aa.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminacrine* / chemistry
  • Aminacrine* / metabolism
  • Aminacrine* / therapeutic use
  • Animals
  • Humans
  • Models, Molecular
  • Molecular Probes* / chemistry
  • Molecular Probes* / metabolism
  • Molecular Probes* / therapeutic use
  • Molecular Structure
  • Nuclear Magnetic Resonance, Biomolecular
  • Prion Diseases / therapy*
  • Prions* / chemistry
  • Prions* / genetics
  • Prions* / metabolism
  • Protein Conformation*
  • Quinacrine* / chemistry
  • Quinacrine* / metabolism
  • Quinacrine* / therapeutic use

Substances

  • Molecular Probes
  • Prions
  • Aminacrine
  • Quinacrine