Binding enthalpy guides a kinase-derived scaffold into potent transthyretin amyloid stabilizers
- A kinase-inhibitor scaffold was repurposed to hold the transthyretin tetramer together, using simplification of the core, tweaks to the terminal phenyl and halogen placement.
- Calorimetry showed gains came mainly from enthalpy, with binding free energy shifting only slightly.
- X-ray and neutron structures point to better shape fit and weak contacts, not classic hydrogen bonds; the lead retains strong binding in human plasma and rivals clinical stabilizers in blocking aggregation.
💡 Points Based on the abstract
Enthalpy works as a design handle only if the gains survive enthalpy-entropy compensation, and a nearly flat free energy is exactly where that bites. I'd want matched pairs isolating the halogen effect, plus data on common destabilizing variants and selectivity over other plasma thyroxine binders, before calling this a better chemotype than the existing benzoxazole-type stabilizers.