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

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.

血浆蛋白转甲状腺素蛋白（transthyretin, TTR）与人类淀粉样变性密切相关。其天然四聚体组装体的解离是天然结构向病理性淀粉样折叠转化过程中的限速步骤。小分子配体结合TTR的甲状腺素结合位点可稳定其四聚体结构，这是一种潜在的治疗策略。然而，通过对9种不同的四聚体稳定配体进行表征，我们发现配体与血浆成分的非特异性结合可能会显著削弱配体的药效。令人意外的是，特定配体与TTR之间的结合强度与其在血浆中的选择性并无显著相关性。不过，通过等温滴定量热法（isothermal titration calorimetry）分析相互作用的热力学特征，我们发现配体的选择性与相互作用的焓变组分之间存在更好的相关性。这一发现对于开发更高效的TTR稳定剂具有重要意义，而高选择性几乎是药物设计中普遍追求的特性，该研究结果可能对药物研发产生广泛影响。