Anticalins engineered for high affinity and specificity towards the central VFFAED epitope in Aβ peptides potently inhibit their aggregation, thus providing novel reagents to study the molecular pathology of Alzheimer's disease (AD) and alternative drug candidates compared with current biopharmaceutical treatments.

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We describe the structural analysis of two Anticalin® proteins that tightly bind Aβ 40, a peptide involved in the pathophysiology of Alzheimer’s disease. These anticalins, US7 and H1GA, were engineered on the basis of the human lipocalin 2, thus yielding compact single-domain binding proteins as an alternative to antibodies. Albeit selected under different conditions and mutually deviating in 13 amino acid positions within the binding pocket (of 17 mutated residues in total), both crystallised anticalins recognize the same epitope in the middle of the β-amyloid peptide. In the two complexes with the Aβ 40 peptide, its central part comprising residues LysP16 to LysP28 shows well defined electron density whereas the flanking regions appear structurally disordered. The compact zigzag-bend conformation which is seen in both structures may indicate a role during conversion of the soluble monomeric form into pathogenic Aβ state(s) and, thus, explain the aggregation-inhibiting effect of the anticalins. In contrast to solanezumab, which targets the same Aβ region in a different conformation, the anticalin H1GA does not show cross-reactivity with sequence-related human plasma proteins. Consequently, anticalins offer promising reagents to prevent oligomerization of Aβ peptides to neurotoxic species in vivo and their small size may enable new routes for brain delivery.

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