Stabilisation of the circulating protein transthyretin is a key approach for preventing its breakdown into amyloid in genetic forms of transthyretin amyloidosis (ATTR) resulting in devastating, multi-organ failure – and also in the heart during normal ageing. Prof Corazza and colleagues demonstrated short- and long-range effects on transthyretin protein structure upon binding of novel, heterobivalent small-molecule stabilising ligands. Using new applications of solution-state nuclear magnetic resonance (NMR) techniques, they showed that the currently marketed drug for ATTR, Pfizer’s tafamidis, binds only at one of two potential binding sites in the transthyretin molecule, and that the bivalent ligands instead thread right through the transthyretin molecule, producing substantially enhanced stabilisation.
The UCL Technology Fund is supporting further development of these bivalent ligands, with the aim of delivering an orally dosed drug to prevent this family of diseases.
More information can be found on the ACSPublications website.