Interactions of tolcapone analogues as stabilizers of the amyloidogenic protein transthyretin

3-O-methyltolcapone and Its Lipophilic Analogues are Potent Inhibitors of Transthyretin Amyloidogenesis with High Permeability and Low Toxicity

“…Binding Interactions between 1 and WT Human TTR. The crystal structure of the TTR/1 complex, determined at 1.19 Å resolution, reveals the so-called "forward binding mode" (Figure 6), characterised by the position of the polar moiety of the 3-methoxy-4-hydroxy-5-nitrophenyl ring in the outermost part of the binding cavity (Figure 6), as already reported for the TTRtolcapone complex [15] and for the 3-OMT complex [40]. The root-mean-square deviation (rmsd) of the Cα atoms between equivalent residues (116 in total) in the monomer of the TTR/1 complex and in the tolcapone and 3-OMT complexes is 0.319 Å and 0.175 Å, respectively.…”

“…Blot procedure [40], with some modifications as follows. Aliquots of human plasma were diluted 8-fold in sodium phosphate buffer (NaP 40 mM, NaCl 150 mM pH 7.4) supplemented with 2 µM or 20 µM of each ligand.…”

“…So, in the present work, starting from the previously reported structure-activity relationships of 3-OMT in complex with TTR [40], we proceeded to design five 3-OMT analogues (Figure 1B).…”

“…In 2020, we reported the synthesis of 3-OMT and 3-deoxytolcapone as potential TTR stabilizers, establishing structure-activity relationships for both molecules, for which, the lack of a free 3-hydroxy group would impede glucuronidation [40]. On the basis of a Western Blot analysis, in the presence of plasma proteins, 3-OMT were more effective and selective in comparison to 3-deoxytolcapone stabilizing the tetrameric native structure of human plasma TTR, and with comparable results to those of tolcapone, in agreement with their very similar chemical structures and the limited differences in their interactions with TTR [40]. The methylation of the free 3-hydroxy group in tolcapone should also confer greater lipophilicity in comparison to tolcapone, thus potentially increasing brain permeability for the pharmacological therapy of CNS TTR amyloidosis (leptomeningeal and oculo-leptomeningeal amyloidosis).…”

“…So, in the present work, starting from the previously reported structure-activity relationships of 3-OMT in complex with TTR [40], we proceeded to design five 3-OMT analogues (Figure 1B). While recently reported new tolcapone analogues conserve its 3-4-dihydroxy-5-nitrophenyl ring but present modifications in the non-phenolic aromatic ring to achieve the highest affinities [18], our analogues maintain the 4-hydroxy-3-methoxy-5-nitrophenyl of 3-OMT to avoid glucuronidation and focus on the non-phenolic aromatic ring of tolcapone to achieve lower toxicity and greater permeability and lipophilicity, without worsening the affinity.…”