Led by Professor Salvador Ventura of the Institute of Biotechnology and Biomedicine at the Universitat Autònoma de Barcelona, an international research team has developed a new experimental approach that clarifies how genetic mutations destabilize the protein transthyretin, a process that underlies transthyretin amyloidosis. Working alongside collaborators from Washington University in St. Louis, the researchers combined advanced mass spectrometry techniques to capture protein behavior that had previously remained inaccessible, providing a more precise framework for mutation-specific drug design.
Professor Salvador Ventura of the Institute of Biotechnology and Biomedicine at the Universitat Autònoma de Barcelona stated,
“By applying mass spectrometry (MS) combined with two biochemical techniques, such as hydrogen-deuterium exchange (HDX) and fast photochemical oxidation of proteins (FPOP), we were able to observe the changes in conformation induced by both mutations and ligand binding, which are invisible to X-ray crystallography.”
Transthyretin, commonly known as TTR, is a transport protein produced mainly in the liver and responsible for carrying thyroid hormones and retinol-binding protein through the bloodstream. In individuals with certain inherited or age-related mutations, TTR becomes structurally unstable, misfolds, and aggregates into amyloid fibrils. These deposits accumulate in organs such as the heart and peripheral nerves, leading to transthyretin amyloidosis, a progressive and often fatal disease with limited treatment options.
Although more than 300 high-resolution TTR structures have been resolved using X-ray crystallography, these structures provide static representations that do not fully explain how pathogenic mutations disrupt protein stability. They also fail to capture how stabilizing drugs interact differently with mutated forms of TTR. As a result, existing therapies tend to act broadly, without accounting for the molecular differences that drive distinct clinical outcomes among patients.
To address this limitation, the research team combined mass spectrometry with hydrogen–deuterium exchange and fast photochemical oxidation of proteins, two complementary techniques capable of monitoring protein dynamics in solution. This approach allowed the researchers to observe how TTR changes shape and flexibility in response to both mutations and ligand binding, offering a dynamic view more comparable to a molecular “movie” than a static image.
Using this methodology, the team analyzed several disease-associated TTR variants and assessed how small-molecule stabilizers interact with them. The results showed that pathogenic mutations weaken key stabilizing interactions within the TTR tetramer, increasing the likelihood of dissociation and aggregation. Importantly, the effectiveness of stabilizing ligands depended on how well they counteracted the specific dynamic disturbances introduced by each mutation.
These findings help explain why current drugs can slow disease progression in some patients but offer limited benefit in others. Approved therapies bind to TTR in a largely uniform manner, without addressing the mutation-specific mechanisms that drive instability. By revealing these hidden destabilization pathways, the study suggests that future drugs should be designed with an explicit focus on the dynamic properties of individual TTR variants.
According to the researchers, integrating mass spectrometry–based techniques into early-stage drug discovery could significantly improve the precision of therapies aimed at preventing amyloid formation. Rather than relying on one-size-fits-all stabilizers, this strategy would enable the development of compounds tailored to the molecular behavior of specific disease-causing mutations.
Adrian graduated with a Masters Degree (1st Class Honours) in Chemical Engineering from Chester University along with Harris. His master’s research aimed to develop a standardadised clean water oxygenation transfer procedure to test bubble diffusers that are currently used in the wastewater industry commercial market. He has also undergone placments in both US and China primarely focused within the R&D department and is an associate member of the Institute of Chemical Engineers (IChemE).
