AI Article Synopsis

  • Transthyretin (TTR) is a protein linked to familial amyloid polyneuropathy (FAP), and discovering stabilizers for its tetramer is key for treatment.
  • Benzbromarone (BBM), originally a uricosuric drug, has been found to effectively stabilize TTR and inhibit amyloid fibril formation, showing properties similar to existing treatments like iododiflunisal (IDIF) and tafamidis.
  • BBM binds to the TTR central channel and enhances tetramer stability, making it a promising candidate for future drug development against TTR-related diseases.

Article Abstract

Transthyretin (TTR) is a homotetrameric protein involved in human amyloidosis, including familial amyloid polyneuropathy (FAP). Discovering small-molecule stabilizers of the TTR tetramer is a therapeutic strategy for these diseases. Tafamidis, the only approved drug for FAP treatment, is not effective for all patients. Herein, we discovered that benzbromarone (BBM), a uricosuric drug, is an effective TTR stabilizer and inhibitor against TTR amyloid fibril formation. BBM rendered TTR more resistant to urea denaturation, similarly to iododiflunisal (IDIF), a very potent TTR stabilizer. BBM competes with thyroxine for binding in the TTR central channel, with an IC similar to IDIF and tafamidis. Results obtained by isothermal titration calorimetry (ITC) demonstrated that BBM binds TTR with an affinity similar to IDIF, tolcapone and tafamidis, confirming BBM as a potent binder of TTR. The crystal structure of the BBM-TTR complex shows two molecules binding deeply in the thyroxine binding channel, forming strong intermonomer hydrogen bonds and increasing the stability of the TTR tetramer. Finally, kinetic analysis of the ability of BBM to inhibit TTR fibrillogenesis at acidic pH and comparison with other stabilizers revealed that benzbromarone is a potent inhibitor of TTR amyloidogenesis, adding a new interesting scaffold for drug design of TTR stabilizers.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583827PMC
http://dx.doi.org/10.3390/ijms21197166DOI Listing

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