title: Ortho-methylated 3-hydroxypyridines hinder hen egg-white lysozyme fibrillogenesis.
abstract: 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.
authors.affiliation: Institut Universitari d'Investigació en Ciències de la Salut (IUNICS). Departament de Química, Universitat de les Illes Balears, Ctra. Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Mariño
authors.affiliation: 1] Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel, Belgium [2] VIB Structural Biology Research Centre, Vlaams Instituut voor Biotechnologie, Pleinlaan 2, 1050 Brussel, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Pauwels
authors.affiliation: Institut Universitari d'Investigació en Ciències de la Salut (IUNICS). Departament de Química, Universitat de les Illes Balears, Ctra. Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Casasnovas
authors.affiliation: Institut Universitari d'Investigació en Ciències de la Salut (IUNICS). Departament de Química, Universitat de les Illes Balears, Ctra. Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sanchis
authors.affiliation: Institut Universitari d'Investigació en Ciències de la Salut (IUNICS). Departament de Química, Universitat de les Illes Balears, Ctra. Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain.
authors.forename: Bartolomé
authors.initials: B
authors.lastname: Vilanova
authors.affiliation: Institut Universitari d'Investigació en Ciències de la Salut (IUNICS). Departament de Química, Universitat de les Illes Balears, Ctra. Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Muñoz
authors.affiliation: Institut Universitari d'Investigació en Ciències de la Salut (IUNICS). Departament de Química, Universitat de les Illes Balears, Ctra. Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain.
authors.forename: Josefa
authors.initials: J
authors.lastname: Donoso
authors.affiliation: Institut Universitari d'Investigació en Ciències de la Salut (IUNICS). Departament de Química, Universitat de les Illes Balears, Ctra. Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain.
authors.forename: Miquel
authors.initials: M
authors.lastname: Adrover
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D018625:Microscopy, Atomic Force / Q000379:methods; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009113:Muramidase / Q000737:chemistry / Q000378:metabolism*; D066329:Protein Aggregates / Q000187:drug effects; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D000682:Amyloid; D066329:Protein Aggregates; D011725:Pyridines; C023500:3-hydroxypyridine; C421864:hen egg lysozyme; D009113:Muramidase