Research ArticleFAMILIAL CARDIAC Amyloidosis

Potent Kinetic Stabilizers That Prevent Transthyretin-Mediated Cardiomyocyte Proteotoxicity

Science Translational Medicine  24 Aug 2011:
Vol. 3, Issue 97, pp. 97ra81
DOI: 10.1126/scitranslmed.3002473

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Thwarting Amyloid by Encouraging Good Behavior

Many proteins can self-assemble into amyloid, protein aggregates that show pronounced β sheet structure, and some of these aggregates accumulate in older people and people with various diseases. Although the β-amyloid of Alzheimer’s disease is the best-known disease-related amyloid, a circulating protein called transthyretin also forms amyloid. When aggregates of transthyretin, which normally carries thyroxine and retinol in the blood, are present in the heart, a serious cardiomyopathy ensues. Stabilization of the normal, tetrameric form of transthyretin prevents dissociation, the first step in amyloid formation. Several drugs that stabilize the tetramer are being tested in clinical trials, but because these drugs resemble nonsteroidal anti-inflammatory agents, they also inhibit the cyclooxygenase (COX) enzymes, causing gastrointestinal distress or cardiovascular problems. New drugs without these side effects are needed to fill this pipeline, and Alhamadsheh and colleagues now present a number of promising candidates discovered through a high-throughput, fluorescence-based screen.

With their assay, the authors could detect, by virtue of a change in the tumbling rate, the binding of a fluorescence-tagged ligand to a site on transthyretin known to control the dissociation of the native tetramer and therefore amyloidogenesis. About 130,000 small-molecule drug candidates were rapidly applied in this system, and their ability to displace the ligand was easily assessed. The top 33 candidates were further validated in an independent surface plasmon resonance assay. Of these, four were able to effectively slow fibril formation to a greater extent than diclofenac, a nonsteroidal anti-inflammatory agent that blocks transthyretin aggregation, and several showed little inhibition of COX-1 enzyme activity, suggesting that they would not have the undesirable side effects of standard nonsteroidal anti-inflammatory agents. The authors identified the structural features that made for good candidate drugs with x-ray crystallography, finding that a flexible ring arrangement with which the ligand could bind and bridge two adjacent subunits was key.

But how do we know that these molecules will work in patients? A definitive answer to that question will require clinical trials, but the authors present some encouraging data. In human cardiomyocytes that are sensitive to transthyretin amyloid, resulting in a decrease of their metabolic activity, the top drug candidates were able to rescue the cells at clinically reasonable concentrations. The top candidates were also effective in the presence of blood proteins, a requirement for a useful drug. Although more work is required, the fruits of this high-throughput screen provide a treasure trove of drugs to enable progress toward successful treatment of the transthyretin amyloidoses, without intestinal or cardiovascular side effects.


  • * These authors contributed equally to this work.

  • Citation: M. M. Alhamadsheh, S. Connelly, A. Cho, N. Reixach, E. T. Powers, D. W. Pan, I. A. Wilson, J. W. Kelly, I. A. Graef, Potent Kinetic Stabilizers That Prevent Transthyretin-Mediated Cardiomyocyte Proteotoxicity. Sci. Transl. Med. 3, 97ra81 (2011).