Enthalpic Forces Correlate with Selectivity of Transthyretin-Stabilizing Ligands in Human Plasma
2015 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 58, no 16, 6507-6515 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2015. Vol. 58, no 16, 6507-6515 p.
transthyretin, entalpic, enthropic
Research subject biological chemistry
IdentifiersURN: urn:nbn:se:umu:diva-106724DOI: 10.1021/acs.jmedchem.5b00544ISI: 000360415800015PubMedID: 26214366OAI: oai:DiVA.org:umu-106724DiVA: diva2:844283