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

Author:
Vöpel, Tobias, Bravo-Rodriguez, Kenny, Mittal, Sumit, Vachharajani, Shivang, Gnutt, David, Sharma, Abhishek, Steinhof, Anne, Fatoba, Oluwaseun, Ellrichmann, Gisa, Nshanian, Michael, Heid, Christian, Loo, Joseph A., Klärner, Frank-Gerrit, Schrader, Thomas, Bitan, Gal, Wanker, Erich E., Ebbinghaus, Simon, Sanchez-Garcia, Elsa
Source:
Journal of the American Chemical Society 2017 v.139 no.16 pp. 5640-5643
ISSN:
1520-5126
Subject:
computer simulation, glutamine, neurodegenerative diseases, toxicity
Abstract:
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.
Agid:
5677909