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Exploiting the Therapeutic Potential of 8‑β‑d‑Glucopyranosylgenistein: Synthesis, Antidiabetic Activity, and Molecular Interaction with Islet Amyloid Polypeptide and Amyloid β‑Peptide (1–42)

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journal contribution
posted on 26.11.2014, 00:00 by Ana R. Jesus, Catarina Dias, Ana M. Matos, Rodrigo F. M. de Almeida, Ana S. Viana, Filipa Marcelo, Rogério T. Ribeiro, Maria P. Macedo, Cristina Airoldi, Francesco Nicotra, Alice Martins, Eurico J. Cabrita, Jesús Jiménez-Barbero, Amélia P. Rauter
8-β-d-Glucopyranosylgenistein (1), the major component of Genista tenera, was synthesized and showed an extensive therapeutical impact in the treatment of STZ-induced diabetic rats, producing normalization of fasting hyperglycemia and amelioration of excessive postprandial glucose excursions and and increasing β-cell sensitivity, insulin secretion, and circulating insulin within 7 days at a dose of 4 (mg/kg bw)/day. Suppression of islet amyloid polypeptide (IAPP) fibril formation by compound 1 was demonstrated by thioflavin T fluorescence and atomic force microscopy. Molecular recognition studies with IAPP and Aβ1–42 employing saturation transfer difference (STD) confirmed the same binding mode for both amyloid peptides as suggested by their deduced epitope. Insights into the preferred conformation in the bound state and conformers’ geometry resulting from interaction with Aβ1–42 were also given by STD, trNOESY, and MM calculations. These studies strongly support 8-β-d-glucopyranosylgenistein as a promising molecular entity for intervention in amyloid events of both diabetes and the frequently associated Alzheimer’s disease.

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