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Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer

Cotrina, Ellen Y ; Oliveira, Ângela ; Leite, José Pedro ; Llop, Jordi ; Gales, Luis ; Quintana, Jordi ; Cardoso, Isabel ; Arsequell, Gemma

International journal of molecular sciences, 2020-10, Vol.21 (19), p.7166 [Periódico revisado por pares]

Switzerland: MDPI AG

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Título:
Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer
Autor: Cotrina, Ellen Y ; Oliveira, Ângela ; Leite, José Pedro ; Llop, Jordi ; Gales, Luis ; Quintana, Jordi ; Cardoso, Isabel ; Arsequell, Gemma
Assuntos: Alzheimer's disease ; Amyloid - antagonists & inhibitors ; Amyloidogenesis ; Amyloidosis ; benzbromarone ; Benzbromarone - chemistry ; Benzbromarone - metabolism ; Benzoxazoles - chemistry ; Benzoxazoles - metabolism ; Binding ; Binding Sites ; Binding, Competitive ; Bonding strength ; Calorimetry ; Complications and side effects ; Crystal structure ; Crystallography, X-Ray ; Denaturation ; Diflunisal - analogs & derivatives ; Diflunisal - chemistry ; Diflunisal - metabolism ; Dosage and administration ; drug ; Drug development ; Drug Repositioning ; drug repurposing ; Fibrillogenesis ; Gene Expression ; Humans ; Hydrogen Bonding ; Hydrogen bonds ; Inhibitors ; Kinetics ; Ligands ; Molecular Docking Simulation ; native kinetic stabilization ; Neuroprotective Agents - chemistry ; Neuroprotective Agents - metabolism ; Patient outcomes ; Polyneuropathy ; Prealbumin - agonists ; Prealbumin - chemistry ; Prealbumin - genetics ; Prealbumin - metabolism ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; Protein Multimerization ; Protein Stability ; Proteins ; R&D ; Recombinant Proteins - chemistry ; Recombinant Proteins - genetics ; Recombinant Proteins - metabolism ; Research & development ; Stability analysis ; Thermodynamics ; Thyroid gland ; Thyroxine ; Thyroxine - chemistry ; Thyroxine - metabolism ; Titration ; Tolcapone ; Tolcapone - chemistry ; Tolcapone - metabolism ; Transthyretin ; transthyretin tetramer stabilizer ; Urea ; Uricosuric agents
É parte de: International journal of molecular sciences, 2020-10, Vol.21 (19), p.7166
Notas: ObjectType-Article-1
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These authors contributed equally to this work.
Descrição: 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.
Editor: Switzerland: MDPI AG
Idioma: Inglês

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Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer

Cotrina, Ellen Y ; Oliveira, Ângela ; Leite, José Pedro ; Llop, Jordi ; Gales, Luis ; Quintana, Jordi ; Cardoso, Isabel ; Arsequell, Gemma

Switzerland: MDPI AG

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