Aminothienopyridazines and Methylene Blue Affect Tau Fibrillization via Cysteine Oxidation

Abstract

Background: Tau fibrillization inhibitors hold promise as potential therapeutic agents for neurodegenerative disease. Results: The Tau fibrillization inhibitors, aminothienopyridazines and methylene blue, promote disulfide bond formation in Tau. Conclusion: These compounds affect Tau fibrillization by a relatively nonspecific oxidative mechanism. Significance: Understanding the mechanism by which these compounds affect Tau fibril formation provides insights into their potential as therapeutic agents.

Structural Determinants of Tau Aggregation Inhibitor Potency

“…Some compounds foster this reaction when incubated with Tau under non-reducing conditions (21). To assess the contribution of Cys residues to cyanine activity, the interaction of 2N4R C291A,C322A…”

“…For example, aldehydes can covalently modify Tau protein monomer, thereby trapping it in aggregation incompetent forms (19). Other compounds promote Cys oxidation under non-reducing conditions and extended incubation times, again yielding assembly incompetent monomer (20,21). Neither of these covalent mechanisms is predicted to have utility in vivo.…”

Pan-Assay Interference Compounds (PAINS): Warning Signs in Biochemical-Pharmacological Evaluations

“…These compoundscould interfere in readouts by multiple ways including: nonselective reactivity with proteins [2] fluorescence [3], cysteine oxidation [4], aggregation [5], redox activity [6], membrane disruption [7] and chelation [8] among others.PAINS are commonly reported in the literature as promising hits against different proteins; however, an accurate look in chemical structure can help biochemists and pharmacologists to identify these structures before testing them.…”

Tau aggregation inhibitors: the future of Alzheimer’s pharmacotherapy?

“…[4] Other redox-active compounds, including the non-neuroleptic phenothiazine methylene blue (MB) [methylthioninium chloride (MTC), Rember™, TRx-0014, TauRx Therapeutics, Singapore, Republic of Singapore] can also modulate cysteine oxidation when incubated in the absence of exogenous reducing agents. [7] In general, covalent mechanisms of tau-aggregation inhibition in AD are predicted to have low utility in vivo. [8] However, dimethylfumarate, an electrophile capable of reacting covalently with cysteine sulfhydryls, was approved for oral treatment of multiple sclerosis, [9] suggesting that electrophilic compounds acting through covalent inhibitory mechanisms can be useful therapeutic agents.…”