Enthalpic Forces Correlate with the Selectivity of Transthyretin-Stabilizing Ligands in Human Plasma

J Med Chem. 2015 Aug 27;58(16):6507-15. doi: 10.1021/acs.jmedchem.5b00544. Epub 2015 Aug 11.

Abstract

The plasma protein transthyretin (TTR) is linked to human amyloidosis. Dissociation of its native tetrameric assembly is a rate-limiting step in the conversion from a native structure into a pathological amyloidogenic fold. Binding of small molecule ligands within the thyroxine binding site of TTR can stabilize the tetrameric integrity and is a potential therapeutic approach. However, through the characterization of nine different tetramer-stabilizing ligands we found that unspecific binding to plasma components might significantly compromise ligand efficacy. Surprisingly the binding strength between a particular ligand and TTR does not correlate well with its selectivity in plasma. However, through analysis of the thermodynamic signature using isothermal titration calorimetry we discovered a better correlation between selectivity and the enthalpic component of the interaction. This is of specific interest in the quest for more efficient TTR stabilizers, but a high selectivity is an almost universally desired feature within drug design and the finding might have wide-ranging implications for drug design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloidosis / drug therapy
  • Calorimetry
  • Drug Design
  • Humans
  • Ligands
  • Models, Molecular
  • Plasma / chemistry
  • Prealbumin / chemistry*
  • Protein Binding
  • Thermodynamics
  • X-Ray Diffraction

Substances

  • Ligands
  • Prealbumin