Alzheimer's disease is the most common cause of dementia in the elderly, and, at present, there are no effective disease-modifying treatments. A key pathological feature of Alzheimer's disease is the build up of β-amyloid (Aβ) in the early phase, making this process a promising target for therapeutic intervention. However, developing small-molecule drugs that prevent the aggregation of Aβ is highly challenging, because the binding energy that drives protein–protein interactions involved in such processes is often distributed over a large surface area. Reporting in Science, Graef and colleagues now describe an innovative strategy for creating molecules that overcome these difficulties.

The secret of this new strategy lies in the synthesis of small molecules that have dual functions. One end of the bifunctional molecule — which is small enough to reach its biological target — binds tightly to Aβ; the other end binds to a protein chaperone, thereby providing the necessary bulk to prevent Aβ aggregation. Graef and colleagues generated a compound that they dubbed SLF-CR, using Congo Red (CR), a small molecule that is known to function as an amyloid ligand, and a synthetic ligand for the FK506-binding protein (FKBP) chaperone family.

Several measures of inhibition showed that this molecule successfully blocked Aβ accumulation when combined with FKBP, in contrast to SLF-CR alone or CR/FKBP, indicating that recruitment of the chaperone is crucial for inhibition of toxicity. More importantly, the authors showed that this molecule prevented neurotoxicity of aggregated Aβ in vitro: Aβ samples treated with SLF-CR/FKBP were considerably less toxic than untreated samples or those treated with CR/FKBP.

Morphological examination of cultured hippocampal neurons that were treated with SLF-CR/FKBP showed that this combination not only blocked the formation of aggregates, but also prevented changes in cell morphology and cell death induced by Aβ toxicity. Finally, the generation of a series of bifunctional molecules with the aim of improving potency led to the discovery of an inhibitor that had an IC50 of ∼50 nM — lower than that of CR by a factor of ∼40, and of SLF-CR by a factor of ∼6.

The development of further small molecules on the basis of this strategy might therefore lead to promising therapeutics for targeting an early, pre-symptomatic, pathological process in Alzheimer's disease. Moreover, this methodology might be generally applicable in other diseases in which it is desirable to target protein–protein interactions.