ECE2015 Eposter Presentations Diabetes (complications & therapy) (143 abstracts)
Diabetes mellitus as a conformational disease: a novel potential therapeutic approach
Isaac Fernández-Gómez 1 , Marquiza Sablón-Carrazana 1, , Alberto Bencomo 1, , Karina Pasten-Hidalgo 3 , Rosa Angélica Castillo-Rodríguez 3 , Guadalupe Domínguez 5 , Reyna Lara 6 , Luis Felipe Jiménez 6 , Julio Morán 5 , Nelly Altamirano-Bustamante 7 , Sergio Islas-Andrade 1 , Chryslaine Rodríguez-Tanty 2 , Eulalia Garrido-Magaña 4 & Myriam M Altamirano-Bustamante 1
1UIEM, Instituto Mexicano del Seguro Social, Mexico, DF, Mexico; 2Centro de Neurociencias, Habana, Cuba; 3Cátedra Conacyt- Instituto Nacional de Pediatría, Mexico, DF, Mexico; 4Servicio de Endocrinología Instituto Nacional de Pediatría, Mexico, DF, Mexico; 5Instituto de Fisiología Celular–UNAM, Mexico, DF, Mexico; 6Facultad de Ciencia–UNAM, Mexico, DF, Mexico; 7Servicio de Endocrinología, Instituto Nacional de Pediatría, Mexico, DF, Mexico.
Introduction: Type 2 diabetes mellitus is a conformational disease (CD), characterised by deposition (fibrils and cytotoxic oligomers) of the human islet amyloid peptide (hIAPP). CDs have devastating effects on the sufferers and their caregivers, as well as a tremendous economic impact on families and the health system. Novel molecule candidates targeting self-assembled amyloidogenic proteins represent a potential therapeutic approach for CDs.
Methods/design: In this work we carried out a systematic study in order to determine the interrelation between the IAPP and IAPP 20–29 fragments in aggregation kinetic with a novel family of naphthalene compounds, used as chemical chaperones. N-(2-aminoethyl)-N′-1-naphthylsuccinamide A; methyl (2-((4-(1-naphthylamino)-4-oxobutanoyl)amino)ethyl) dithiocarbamate B; (2R)-2-(6-methoxy-2-naphthyl)propanoic acid (Naproxen) C; N-(4-(1-naphthylamino)-4-oxobutanoyl)-β-alanine D; 6-((4-(1-naphthylamino)-4-oxobutanoyl)amino) hexanoic acid E; N3,N3′-ethane-1,2-dyilbis(N1-1-naphthylsuccinamide) F; N-(4-aminobutyl)-N′-1-naphthylsuccinamide G; and (1E,6E)-1,8-bis(4-hydroxy-3-methoxyphenyl)octa-1,6-diene-3,5-dione (Curcumine). We describe the structural features, aggregation kinetics, and toxic properties of the, in presence or absence of a novel naphthalene of the chemical chaperones family.
Results: We found a stronger inhibitory effect in the fibril formation of the chaperones B, C, D, E, and G. Transmission electron microscopy showed the presence of long and curly fibers in the sample control, while the samples treated with chaperones A, B. C, D, and E, generated several amorphous and disaggregated structures. A cytoprotective effect of the chaperones family on cerebellar granule cells was found in the MTT assays. Furthermore, the binding sites of the chemical chaperones to hIAPP were located by means of docking on the IAPP 3D model.
Conclusion: In this study we managed to obtain chaperones that bind to the native state, to the cytotoxic oligomers and the amyloid fibrils. Chaperones derived from naphthalene can regulate fibre formation processes by binding to the native state, minimising the formation of amorphous aggregates, as well as cytotoxic oligomers.
Disclosure: Funding for this study was provided by Mexico’s National Council of Science and Technology (CONACYT) SALUD-2010-C02-151942; Cátedras Conacyt and Institute of Science and Technology of Mexico City (ICYTDF).
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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