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Benzoxazoles as Transthyretin Amyloid Fibril Inhibitors: Synthesis, Evaluation, and Mechanism of Action

Authors


  • This work was supported by the NIH (DK 46335), the Skaggs Institute for Chemical Biology, and the Lita Annenberg Hazen Foundation. H.R. thanks the Skaggs Institute for Chemical Biology for a postdoctoral fellowship. Additional support was provided by the Robert A. Welch Foundation (J.C.S). Use of the Argonne National Laboratory Structural Biology Center beam lines at the Advanced Photon Source was supported by the United States Department of Energy, Office of Energy Research, under contract W-31-109-ENG-38. Use of the BioCARS Sector 14 was supported by the National Institutes of Health National Center for Research Resources. We thank the General Clinical Research Center of The Scripps Research Institute (supported by NIH grant RR00833) for providing blood plasma through the normal donor blood drawing program.

Abstract

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Fester Zusammenhalt: Wirkstoffe auf Benzoxazol-Basis zählen zu den effektivsten Inhibitoren der Bildung von Amyloidfibrillen aus Transthyretin (TTR). Zum einen stabilisieren sie TTR gegen Fehlfaltungen infolge Säureeinwirkung, zum anderen vergrößern sie die Aktivierungsbarriere für die Dissoziation der TTR-Tetramere, den geschwindigkeitsbestimmenden Schritt der Amyloidbildung. Unser Bild zeigt die Struktur eines Komplexes von TTR mit einem Benzoxazolinhibitor im Kristall.

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