Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 16, Pages 6507-6515Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00544
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Funding
- Swedish Research Council
- Parkinsonfonden
- Insamlingsstiftelsen vid Umea Universitet
- Alzheimerfonden
- Ahlenstiftelsen
- J. C. Kempes Stiftelse
- Hjarnfonden
- Magnus-Bergvalls Stiftelse
- O.E. och Edlas Stiftelse
- Torsten Soderbergs Stiftelse
- Vasterbottens Lans Lasting (ALF-medel)
- Patientforeningen FAMY/AMYL
- Medical Faculty of Umea University
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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.
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