title: X-ray crystal structure and activity of fluorenyl-based compounds as transthyretin fibrillogenesis inhibitors.
abstract: Transthyretin (TTR) is a 54 kDa homotetrameric protein that transports thyroxine (T4) and retinol (vitamin A), through its association with retinol binding protein (RBP). Under unknown conditions, it aggregates to form fibrils associated with TTR amyloidosis. Ligands able to inhibit fibril formation have been studied by X-ray crystallography. The use of polyethylene glycol (PEG) instead of ammonium sulphate or citrate has been evaluated as an alternative to obtain new TTR complexes with (R)-3-(9-fluoren-9-ylideneaminooxy)-2-methyl-N-(methylsulfonyl) propionamide (48R(1)) and 2-(9H-fluoren-9-ylideneaminooxy) acetic acid (ES8(2)). The previously described fluorenyl based inhibitors (S)-3-((9H-fluoren-9-ylideneamino)oxy)-2-methylpropanoic acid (6BD) and 3-((9H-fluoren-9-ylideneamino)oxy)propanoic acid (7BD) have been re-evaluated with the changed crystallization method. The new TTR complexes with compounds of the same family show that the 9-fluorenyl motif can occupy alternative hydrophobic binding sites. This augments the potential use of this scaffold to yield a large variety of differently substituted mono-aryl compounds able to inhibit TTR fibril formation.
authors.affiliation: a CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO) , Gif-sur-Yvette , France and.|b Dipartimento di Farmacia , Università di Pisa , Pisa , Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Ciccone
authors.affiliation: b Dipartimento di Farmacia , Università di Pisa , Pisa , Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Nencetti
authors.affiliation: b Dipartimento di Farmacia , Università di Pisa , Pisa , Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
authors.affiliation: a CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO) , Gif-sur-Yvette , France and.|b Dipartimento di Farmacia , Università di Pisa , Pisa , Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Tepshi
authors.affiliation: a CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO) , Gif-sur-Yvette , France and.
authors.forename: Enrico A
authors.initials: EA
authors.lastname: Stura
authors.affiliation: b Dipartimento di Farmacia , Università di Pisa , Pisa , Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orlandini
mesh_terms: D020816:Amino Acid Motifs; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018360:Crystallography, X-Ray / Q000379:methods*; D005449:Fluorenes / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry; D011228:Prealbumin / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C000615716:2-(9H-fluoren-9-ylideneaminooxy)acetic acid; C000616076:3-(9-fluoren-9-ylideneaminooxy)-2-methyl-N-(methylsulfonyl); D000682:Amyloid; D005449:Fluorenes; D011228:Prealbumin; D011092:Polyethylene Glycols
keywords: Fibril formation inhibitors; fluorenyl; new crystallization methods; transthyretin