Design of mechanism-based inhibitors of transthyretin amyloidosis:Studies with biphenyl ethers and new structural templates

Gupta, Sarika and Chhibber, Manmohan and Sinha, Sharmistha and Surolia, Avadhesha (2007) Design of mechanism-based inhibitors of transthyretin amyloidosis:Studies with biphenyl ethers and new structural templates. In: Journal of Medicinal Chemistry, 50 (23). pp. 5589-5599.

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Abstract

Transthyretin (TTR), a tetrameric thyroxine (T4) carrier protein, is associated with a variety of amyloid diseases. In this study, we explore the potential of biphenyl ethers (BPE), which are shown to interact with a high affinity to its T4 binding site thereby preventing its aggregation and fibrillogenesis. They prevent fibrillogenesis by stabilizing the tetrameric ground state of transthyretin. Additionally, we identify two new structural templates (2-(5-mercapto-[1,3,4]oxadiazol-2-yl)-phenol and 2,3,6-trichloro-N-(4H-[1,2,4]triazol-3-yl) represented as compounds 11 and 12, respectively, throughout the manuscript) exhibiting the ability to arrest TTR amyloidosis. The dissociation constants for the binding of BPEs and compound 11 and 12 to TTR correlate with their efficacies of inhibiting amyloidosis. They also have the ability to inhibit the elongation of intermediate fibrils as well as show nearly complete (> 90%) disruption of the preformed fibrils. The present study thus establishes biphenyl ethers and compounds 11 and 12 as very potent inhibitors of TTR fibrillization and inducible cytotoxicity.

Item Type:	Journal Article
Publication:	Journal of Medicinal Chemistry
Publisher:	American Chemical Society
Additional Information:	Copyright of this article belongs to American Chemical Society.
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	10 Jun 2010 09:34
Last Modified:	19 Sep 2010 05:56
URI:	http://eprints.iisc.ac.in/id/eprint/26157

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