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Rational design of potent human transthyretin amyloid disease inhibitors

Nature Structural Biology volume 7, pages 312–321 (2000)Cite this article

A Correction to this article was published on 01 May 2000

Abstract

The human amyloid disorders, familial amyloid polyneuropathy, familial amyloid cardiomyopathy and senile systemic amyloidosis, are caused by insoluble transthyretin (TTR) fibrils, which deposit in the peripheral nerves and heart tissue. Several nonsteroidal anti-inflammatory drugs and structurally similar compounds have been found to strongly inhibit the formation of TTR amyloid fibrils in vitro. These include flufenamic acid, diclofenac, flurbiprofen, and resveratrol. Crystal structures of the protein–drug complexes have been determined to allow detailed analyses of the protein–drug interactions that stabilize the native tetrameric conformation of TTR and inhibit the formation of amyloidogenic TTR. Using a structure-based drug design approach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4,6-dicarboxylic acid have been discovered to be very potent and specific TTR fibril formation inhibitors. This research provides a rationale for a chemotherapeutic approach for the treatment of TTR-associated amyloid diseases.

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Figure 1: The hormone binding channel of TTR.
Figure 2: Structures of thyroxine (T4), the natural ligand of TTR, the NSAIDs tested as fibril formation inhibitors (1–9), and designed TTR fibril formation inhibitors (10–12).
Figure 3: Hormone binding site structure of the TTR–RESV complex.
Figure 4: Structure of the TTR–DIC complex.
Figure 5: Comparison of binding of flurbiprofen to TTR and COX-2.
Figure 6: Hormone binding channel of TTR with bound novel designed amyloid inhibitors.

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Acknowledgements

This work is supported by NIH grants (JCS and JWK), the Welch foundation and the Skaggs Institute for Chemical Biology. T.K. thanks the Deutsche Forschungsgemeinschaft for a postdoctoral fellowship.

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  1. Thomas Klabunde

    Present address: Aventis Pharma Germany, Chemical Research, D-65926, Frankfurt, Germany

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, Texas A&M University, College Station, 77843, Texas, USA

    Thomas Klabunde & James C. Sacchettini

  2. Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd. MB 12, La Jolla, 92037, California, USA

    H. Michael Petrassi, Vibha B. Oza, Prakash Raman & Jeffery W. Kelly

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Correspondence to James C. Sacchettini.

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Klabunde, T., Petrassi, H., Oza, V. et al. Rational design of potent human transthyretin amyloid disease inhibitors. Nat Struct Mol Biol 7, 312–321 (2000). https://doi.org/10.1038/74082

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