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(el)). Above a threshold of 37 glutamine residues, httel starts to aggregate in a nucleation-dependent manner. A 17-residue N-terminal fragment of htt(el) (N17) has been suggested to play a crucial role in modulating the aggregation propensity and toxicity of htt(el). 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(el) monomer and inhibits htt(el) aggregation, underpinning the key role of N17 in modulating htt(el) toxicity.