Generic inhibition of amyloidogenic proteins by two naphthoquinone–tryptophan hybrid molecules

Roni Scherzer‐Attali; Ronit Shaltiel‐Karyo; Yonatan H. Adalist; Daniel Segal; Ehud Gazit

doi:10.1002/prot.24080

journal article May 26, 2012

Generic inhibition of amyloidogenic proteins by two naphthoquinone–tryptophan hybrid molecules

Roni Scherzer‐Attali Ronit Shaltiel‐Karyo Yonatan H. Adalist Daniel Segal

Ehud Gazit

Proteins: Structure, Function, and Bioinformatics Vol. 80 No. 8 pp. 1962-1973 · Wiley

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Abstract

AbstractAmyloid formation is associated with several human diseases including Alzheimer's disease (AD), Parkinson's disease, Type 2 Diabetes, and so forth, no disease modifying therapeutics are available for them. Because of the structural similarities between the amyloid species characterizing these diseases, (despite the lack of amino acid homology) it is believed that there might be a common mechanism of toxicity for these conditions. Thus, inhibition of amyloid formation could be a promising disease‐modifying therapeutic strategy for them. Aromatic residues have been identified as crucial in formation and stabilization of amyloid structures. This finding was corroborated by high‐resolution structural studies, theoretical analysis, and molecular dynamics simulations. Amongst the aromatic entities, tryptophan was found to possess the most amyloidogenic potential. We therefore postulate that targeting aromatic recognition interfaces by tryptophan could be a useful approach for inhibiting the formation of amyloids. Quinones are known as inhibitors of cellular metabolic pathways, to have anti‐ cancer, anti‐viral and anti‐bacterial properties and were shown to inhibit aggregation of several amyloidogenic proteins in vitro. We have previously described two quinone‐tryptophan hybrids which are capable of inhibiting amyloid‐beta, the protein associated with AD pathology, both in vitro and in vivo. Here we tested their generic properties and their ability to inhibit other amyloidogenic proteins including α‐synuclein, islet amyloid polypeptide, lysozyme, calcitonin, and insulin. Both compounds showed efficient inhibition of all five proteins examined both by ThT fluorescence analysis and by electron microscope imaging. If verified in vivo, these small molecules could serve as leads for developing generic anti‐amyloid drugs. Proteins 2012; © 2012 Wiley Periodicals, Inc.

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Citations

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References

Details

Published: May 26, 2012
Vol/Issue: 80(8)
Pages: 1962-1973
License: View

Authors

Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.

Cite This Article

Roni Scherzer‐Attali, Ronit Shaltiel‐Karyo, Yonatan H. Adalist, et al. (2012). Generic inhibition of amyloidogenic proteins by two naphthoquinone–tryptophan hybrid molecules. Proteins: Structure, Function, and Bioinformatics, 80(8), 1962-1973. https://doi.org/10.1002/prot.24080

Generic inhibition of amyloidogenic proteins by two naphthoquinone–tryptophan hybrid molecules

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