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oai:repisalud.isciii.es:20.500.12105/201282024-11-28T22:32:03Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967

00925njm 22002777a 4500 dc Marino, Laura author Pauwels, Kris author Casasnovas, Rodrigo author Sanchis, Pilar author Vilanova, Bartolome author Munoz, Francisco author Donoso, Josefa author Adrover, Miquel author 2015-07-14 Protein aggregation with the concomitant formation of amyloid fibrils is related to several neurodegenerative diseases, but also to non-neuropathic amyloidogenic diseases and non-neurophatic systemic amyloidosis. Lysozyme is the protein involved in the latter, and it is widely used as a model system to study the mechanisms underlying fibril formation and its inhibition. Several phenolic compounds have been reported as inhibitors of fibril formation. However, the anti-aggregating capacity of other heteroaromatic compounds has not been studied in any depth. We have screened the capacity of eleven different hydroxypyridines to affect the acid-induced fibrillization of hen lysozyme. Although most of the tested hydroxypyridines alter the fibrillation kinetics of HEWL, only 3-hydroxy-2-methylpyridine, 3-hydroxy-6-methylpyridine and 3-hydroxy-2,6- dimethylpyridine completely abolish fibril formation. Different biophysical techniques and several theoretical approaches are combined to elucidate their mechanism of action. O-methylated 3-hydroxypyridines bind non-cooperatively to two distinct but amyloidogenic regions of monomeric lysozyme. This stabilises the protein structure, as evidenced by enhanced thermal stability, and results in the inhibition of the conformational transition that precedes fibril assembly. Our results point to o-methylated 3-hydroxypyridines as a promising molecular scaffold for the future development of novel fibrillization inhibitors. Mariño Perez L, Pauwels K, Casanovas R, Sanchis P, Vilanova Canet B, Muñoz Izquierdo F, et al. Ortho-methylated 3-hydroxypyridines hinder hen egg-white lysozyme fibrillogenesis. Sci Rep. 2015 Jul 14;5:12052. 10.1038/srep12052 2045-2322 Scientific Reports http://hdl.handle.net/20.500.13003/10778 26169912 L615560413 2-s2.0-84937026811 http://hdl.handle.net/20.500.12105/20128 357862600001 Ortho-methylated 3-hydroxypyridines hinder hen egg-white lysozyme fibrillogenesis