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Author Batlle González, Cristina |
Abstract An amyloidosis is a group of degenerative diseases that affect the peripheral nerves and alter the normal function of vital organs, caused by a conformational change (mutation) that a number of proteins undergo, due to the abnormal formation of insoluble aggregates (amyloid fibers )). Transthyretin (TTR) is one of the main amyloidogenic proteins. Stabilization of the tetrameric structure of TTR is one of the current pharmacological strategies to prevent hereditary ATTR amyloidoses, such as familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC). The IQS Biochemistry Laboratory has developed a bioassay to evaluate possible TTR inhibitors. In recent years, several families of compounds based on non-steroidal anti-inflammatory drugs (NSAIDs) have been analyzed, obtaining very promising results, as in the case of iododiflunisal. On the other hand, the IQS Pharmaceutical Chemistry research group has designed and synthesized a new family of compounds as potential inhibitors of TTR-associated amyloidosis. Specifically, this project focuses on the design and synthesis of new borylated reversible covalent ligands with a bisboronic biphenyl acid structure, which has been elaborated by means of innovative catalytic reactions with transition metals. The main objective has been to evaluate them as possible TTR inhibitors by means of a bioassay with recombinant human TTR. The TTR fibrillogenesis inhibition assay has shown that bisboronic biphenyl acid inhibits the formation of strands of the highly amyloidogenic variant of the TTR-Y78F protein, almost as effectively as iododiflunisal, a potent inhibitor of TTR amyloidosis. . These results show a new approach in the covalent inhibition of the formation of amyloid fibrils and initiate a new path in the optimization to prevent the disease. |
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Director Cuenca González, Ana Belén |
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Degree IQS SE - Master’s Degree in Pharmaceutical Chemistry |
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Date 2021-09-17
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