Inhibition of Huntingtin Exon-1 Aggregation by the Molecular Tweezer CLR01
Vöpel, T. and Bravo-Rodriguez, K. and Mittal, S. and Vachharajani, S. and Gnutt, D. and Sharma, A. and Steinhof, A. and Fatoba, O. and Ellrichmann, G. and Nshanian, M. and Heid, C. and Loo, J.A. and Klärner, F.-G. and Schrader, T. and Bitan, G. and Wanker, E.E. and Ebbinghaus, S. and Sanchez-Garcia, E.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume: 139 Pages: 5640-5643
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. © 2017 American Chemical Society.