Huntington's disease is a neurodegenerative disorder associated with the expansion of the polyglutamine tract in the exon-1 domain of the huntingtin protein (htt^e1). Above a threshold of 37 glutamine residues, htt^e1 starts to aggregate in a nucleation-dependent manner. A 17-residue N-terminal fragment of htt^e1 (N17) has been suggested to play a crucial role in modulating the aggregation propensity and toxicity of htt^e1. 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 htt^e1 monomer and inhibits htt^e1 aggregation, underpinning the key role of N17 in modulating htt^e1 toxicity.