Document Detail


Selective binding to transthyretin and tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy by an iodinated diflunisal derivative.
MedLine Citation:
PMID:  15080795     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In familial amyloidotic polyneuropathy, TTR (transthyretin) variants are deposited as amyloid fibrils. It is thought that this process involves TTR tetramer dissociation, which leads to partially unfolded monomers that aggregate and polymerize into amyloid fibrils. This process can be counteracted by stabilization of the tetramer. Several small compounds, such as diclofenac, diflunisal and flufenamic acid, have been reported to bind to TTR in vitro, in the T4 (thyroxine) binding channel that runs through the TTR tetramer, and consequently are considered to stabilize TTR. However, if these agents bind plasma proteins other than TTR, decreased drug availability will occur, compromising their use as therapeutic agents for TTR amyloidosis. In the present work, we compared the action of these compounds and of new derivatives designed to increase both selectivity of binding to TTR and inhibitory potency in relation to TTR amyloid fibril formation. We found two diflunisal derivatives that, in contrast with diclofenac, flufenamic acid and diflunisal, displaced T4 from TTR in plasma preferentially over binding to albumin and thyroxine binding globulin. The same diflunisal derivatives also had a stabilizing effect on TTR tetramers in plasma, as studied by isoelectric focusing of whole plasma under semi-denaturing conditions. In addition, by transmission electron microscopy, we demonstrated that, in contrast with other proposed TTR stabilizers (namely diclofenac, flufenamic acid and diflunisal), one of the diflunisal derivatives tested efficiently inhibited TTR aggregation. Taken together, our ex vivo and in vitro studies present evidence for the selectivity and efficiency of novel diflunisal derivates as TTR stabilizers and as inhibitors of fibril formation.
Authors:
Maria Rosário Almeida; Bárbara Macedo; Isabel Cardoso; Isabel Alves; Gregorio Valencia; Gemma Arsequell; Antoni Planas; Maria João Saraiva
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Biochemical journal     Volume:  381     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2004 Jul 
Date Detail:
Created Date:  2004-06-30     Completed Date:  2004-12-20     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  351-6     Citation Subset:  IM    
Affiliation:
Molecular Neurobiology Unit, Instituto de Biologia Molecular e Celular e Departamento de Biologia Molecular, ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4150-180 Porto, Portugal.
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MeSH Terms
Descriptor/Qualifier:
Amyloid Neuropathies / blood*,  genetics*
Diclofenac / chemistry,  metabolism
Diflunisal / analogs & derivatives*,  blood,  chemistry,  metabolism*
Flufenamic Acid / chemistry,  metabolism
Humans
Iodine / blood,  chemistry,  metabolism*
Iodobenzoates / blood,  chemistry,  metabolism
Molecular Structure
Prealbumin / chemistry*,  metabolism*
Protein Binding / genetics
Thyroxine / metabolism
Chemical
Reg. No./Substance:
0/Iodobenzoates; 0/Prealbumin; 15307-86-5/Diclofenac; 22494-42-4/Diflunisal; 530-78-9/Flufenamic Acid; 7488-70-2/Thyroxine; 7553-56-2/Iodine
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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