Metabolic detoxication of bis-(2-hydroxy-3,5-dichlorophenyl)-sulfoxide in man.

Sakamoto, Mieko; Chiba, Kazumoto; Agata, Isao; Higa, Tamotsu; Kiyota, Masato; Hayashi, Nobuyuki; Yagi, Naomi; Itoh, Masashi; Sekikawa, Hitoshi

doi:10.2131/jts.6.307

Cited by 4 publications

(1 citation statement)

References 8 publications

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“…42 was once approved by the FDA but was withdrawn in 1967 due to its dermatologic toxicity. However, the pharmacokinetic profile of the oral dose form of 42 including its safety, toxicity, and mild side effect profileshas already been demonstrated. − In addition, a recent study showed that 42 was able to cross the blood–brain barrier (BBB) in amyloid precursor protein transgenic mice . Such BBB permeability would be a great advantage for the development of inhibitors to treat leptomeningeal amyloidosis, which is characterized by TTR amyloid deposition in the leptomeningeal vessels .…”

Section: Discussionmentioning

confidence: 99%

Repositioning of the Anthelmintic Drugs Bithionol and Triclabendazole as Transthyretin Amyloidogenesis Inhibitors

2021

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Transthyretin (TTR) is a causative protein of TTR amyloidosis (ATTR amyloidosis), a general term for diseases characterized by deposition of TTR amyloid fibrils in specific organs. ATTR amyloidosis can be ameliorated by stabilization of the TTR tetramer through the binding of small molecules. Here, we show that the clinical anthelmintic drugs bithionol (42) and triclabendazole (43) potently inhibit aggregation of the amyloidogenic variant V30M-TTR. A competitive binding assay using a fluorescence probe showed that the binding affinity of 42 with V30M-TTR was significantly higher than that of the first-in-class drug tafamidis (1), and the binding affinity of 43 was similar to that of 1. The crystallographic and thermodynamic analysis revealed that 42 efficiently occupied the halogen-binding grooves of TTR, resulting in the favorable binding entropy. Multifaceted in vitro studies of anthelmintic drugs have the potential to reposition these drugs as ATTR amyloidosis inhibitors.

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