Small transthyretin (TTR) ligands as possible therapeutic agents in TTR amyloidoses

• Type: Another Publication in an International Scientific Journal
• Date: 2005

Authors

Almeida, MR (Author) ICBAS; Gales, L (Author) ICBAS; Damas, AM (Author) Other; Cardoso, I (Author) Other; Saraiva, MJ (Author) ICBAS

Journal

Title: Current Drug Targets: CNS and Neurological Disorders

Vol. 4

Pages: 587-596

ISSN: 1568-007X

Publisher: Bentham Science

Indexing

ISI Web of Knowledge

Scopus - 51 Citations

Other information

Authenticus ID: P-007-E7W

DOI: 10.2174/156800705774322076

Abstract (EN): In transthyretin (TTR) amyloidosis TTR variants deposit as amyloid fibrils giving origin, in most cases, to peripheral polyneuropathy, cardiomyopathy, carpal tunnel syndrome and/or amyloid deposition in the eye. More than eighty TTR variants are known, most of them being pathogenic. The mechanism of TTR fibril formation is still not completely elucidated. However it is widely accepted that the amino acid substitutions in the TTR variants contribute to a destabilizing effect on the TTR tetramer molecule, which in particular conditions dissociate into non native monomeric intermediates that aggregate and polymerize in amyloid fibrils that further elongate. Since this is a multi-step process there is the possibility to impair TTR amyloid fibril formation at different stages of the process namely by tetramer stabilization, inhibition of fibril formation or fibril disruption. Till now the only efficient therapy available is liver transplant when performed in an early phase of the onset of the disease symptoms. Since this is a very invasive therapy alternatives are desirable. In that sense, several compounds have been proposed to impair amyloid formation or disruption. Based on the proposed mechanism for TTR amyloid fibril formation we discuss the action of some of the proposed TTR stabilizers such as derivatives of some NSAIDs (diflunisal, diclofenac, flufenamic acid, and derivatives) and the action of amyloid disrupters such as 4¿-iodo-4¿-deoxydoxorubicin (I-DOX) and tetracyclines. Among all these compounds, TTR stabilizers seem to be the most interesting since they would impair very early the process of amyloid formation and could also have a prophylactic effect. © 2005 Bentham Science Publishers Ltd.

Language: English

Type (Professor's evaluation): Scientific