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Author
Montaner Rey, Cristina
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Abstract
Amyloidosis is a family of diseases that consist of the abnormal folding of a protein that is deposited in the organs in the form of amyloid fibrils, altering their normal functioning. Transthyretin (TTR) is one of the main amyloidogenic proteins present in the body and is the cause of some hereditary amyloidosis such as familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC). One of the current pharmacological strategies to treat these diseases is the stabilization of the tetrameric structure of TTR with the aim of minimizing the initiation of misfolding processes, also known as fibrillogenesis.
Regarding fibrillogenesis inhibitors, different approaches have been adopted: non-covalent, irreversible covalent and reversible covalent inhibitors. In recent years, several borylated compounds within this last category have been studied. These compounds are able to establish a reversible covalent bond with some TTR residues and thus stabilizing the tetramer of the protein.
The borylated species studied so far targeted the Serine and Threonine residues of the protein. However, this Final Degree Project focuses on the synthesis and biological evaluation of a borylated compound derived from 2-aminobenzaldehyde as a possible reversible covalent inhibitor targeted to Lysine of the TTR binding site. In the TTR fibrillogenesis inhibition assay, the new borylated compound has shown to be able to inhibit the formation of fibrils of the highly amyloidogenic variant TTR – Y78F almost as effectively as iododiflunisal, a potent inhibitor of TTR amyloidosis.
These findings open the door to a new approach in reversible covalent inhibition of amyloid fibril formation and to a new family of inhibitors to treat TTR-associated amyloidosis.
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