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Inhibition of Huntingtin Exon-1 Aggregation by the Molecular Tweezer CLR01

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    Inhibition of Huntingtin Exon-1 Aggregation by the Molecular Tweezer CLR01
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    † Department of Physical Chemistry II, Ruhr-University Bochum, 44780 Bochum, Germany
    ‡ Max-Planck-Institut für Kohlenforschung, 45470 Mülheim an der Ruhr, Germany
    § Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany
    ∥ Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44780 Bochum, Germany
    ⊥ Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, California 90095, United States
    # Department of Biological Chemistry and UCLA/DOE Institute of Genomics and Proteomics, University of California at Los Angeles, Los Angeles, California 90095, United States
    ∇ Institute of Organic Chemistry, University of Duisburg-Essen, 45141 Essen, Germany
    ○ Department of Neurology, David Geffen School of Medicine, Brain Research Institute, and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095-7334, United States
    *[email protected]
    *[email protected]
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    Cite this: J. Am. Chem. Soc. 2017, 139, 16, 5640–5643
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    https://doi.org/10.1021/jacs.6b11039
    Published April 13, 2017
    Copyright © 2017 American Chemical Society
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    Abstract

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    Huntington’s disease is a neurodegenerative disorder associated with the expansion of the polyglutamine tract in the exon-1 domain of the huntingtin protein (htte1). Above a threshold of 37 glutamine residues, htte1 starts to aggregate in a nucleation-dependent manner. A 17-residue N-terminal fragment of htte1 (N17) has been suggested to play a crucial role in modulating the aggregation propensity and toxicity of htte1. Here we identify N17 as a potential target for novel therapeutic intervention using the molecular tweezer CLR01. A combination of biochemical experiments and computer simulations shows that binding of CLR01 induces structural rearrangements within the htte1 monomer and inhibits htte1 aggregation, underpinning the key role of N17 in modulating htte1 toxicity.

    Copyright © 2017 American Chemical Society

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    Cite this: J. Am. Chem. Soc. 2017, 139, 16, 5640–5643
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.6b11039
    Published April 13, 2017
    Copyright © 2017 American Chemical Society
    Request reuse permissions

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