Transthyretin (TTR) is one of thirty non-homologous proteins whose misfolding, dissocn., aggregation, and deposition is linked to human amyloid diseases. Previous studies have identified that TTR amyloidogenesis can be inhibited through stabilization of the native tetramer state by small mol. binding to the thyroid hormone sites of TTR. We have evaluated a new series of b-aminoxypropionic acids (compds. 5-21), with a single arom. moiety (aryl or fluorenyl) linked through a flexible oxime tether to a carboxylic acid. These compds. are structurally distinct from the native ligand thyroxine and typical halogenated biaryl NSAID-like inhibitors to avoid off-target hormonal or anti-inflammatory activity. Based on an in vitro fibril formation assay, five of these compds. showed significant inhibition of TTR amyloidogenesis, with two fluorenyl compds. displaying inhibitor efficacy comparable to the well-known TTR inhibitor diflunisal. Fluorenyl 15 is the most potent compd. in this series and importantly does not show off-target antiinflammatory activity. Crystal structures of the TTR:inhibitor complexes, in agreement with mol. docking studies, revealed that the arom. moiety, linked to the sp2-hybridized oxime carbon, specifically directed the ligand in either a forward or reverse binding mode. Compared to the aryl family members, the bulkier fluorenyl analogs achieved more extensive interactions with the binding pockets of TTR and demonstrated better inhibitory activity in the fibril formation assay. Preliminary optimization efforts are described that focused on replacement of the C-terminal acid in both the aryl and fluorenyl series (compds. 22-32). The compds. presented here constitute a new class of TTR inhibitors that may hold promise in treating amyloid diseases assocd. with TTR misfolding.

Novel Transthyretin Amyloid Fibril Formation Inhibitors: Synthesis, Biological Evaluation, and X-Ray Structural Analysis

ORLANDINI, ELISABETTA;ORTORE, GABRIELLA MARIA PIA;NENCETTI, SUSANNA;LAPUCCI, ANNALINA;ROSSELLO, ARMANDO;
2009-01-01

Abstract

Transthyretin (TTR) is one of thirty non-homologous proteins whose misfolding, dissocn., aggregation, and deposition is linked to human amyloid diseases. Previous studies have identified that TTR amyloidogenesis can be inhibited through stabilization of the native tetramer state by small mol. binding to the thyroid hormone sites of TTR. We have evaluated a new series of b-aminoxypropionic acids (compds. 5-21), with a single arom. moiety (aryl or fluorenyl) linked through a flexible oxime tether to a carboxylic acid. These compds. are structurally distinct from the native ligand thyroxine and typical halogenated biaryl NSAID-like inhibitors to avoid off-target hormonal or anti-inflammatory activity. Based on an in vitro fibril formation assay, five of these compds. showed significant inhibition of TTR amyloidogenesis, with two fluorenyl compds. displaying inhibitor efficacy comparable to the well-known TTR inhibitor diflunisal. Fluorenyl 15 is the most potent compd. in this series and importantly does not show off-target antiinflammatory activity. Crystal structures of the TTR:inhibitor complexes, in agreement with mol. docking studies, revealed that the arom. moiety, linked to the sp2-hybridized oxime carbon, specifically directed the ligand in either a forward or reverse binding mode. Compared to the aryl family members, the bulkier fluorenyl analogs achieved more extensive interactions with the binding pockets of TTR and demonstrated better inhibitory activity in the fibril formation assay. Preliminary optimization efforts are described that focused on replacement of the C-terminal acid in both the aryl and fluorenyl series (compds. 22-32). The compds. presented here constitute a new class of TTR inhibitors that may hold promise in treating amyloid diseases assocd. with TTR misfolding.
2009
Palaninathan, S. K.; Mohamedmohaideen, N. N.; Orlandini, Elisabetta; Ortore, GABRIELLA MARIA PIA; Nencetti, Susanna; Lapucci, Annalina; Rossello, Armando; FREUNDLINCH JL, S; Sacchettini, J. C.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/196581
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