Discovery of Novel Inhibitors of Amyloid β‑Peptide 1–42 Aggregation

Alzheimer's disease, characterized by deposits of amyloid β-peptide (Aβ), is the most common neurodegenerative disease, but it still lacks a specific treatment. We have discovered five chemically unrelated inhibitors of the in vitro aggregation of the Aβ17–40 peptide by screening two commercial chemical libraries. Four of them (1–4) exhibit relatively low MCCs toward HeLa cells (17–184 μM). The usefulness of compounds 1–4 to inhibit the in vivo aggregation of Aβ1–42 has been demonstrated using two fungi models, Saccharomyces cerevisiae and Podospora anserina, previously transformed to express Aβ1–42. Estimated IC50s are around 1–2 μM. Interestingly, addition of any of the four compounds to sonicated preformed P. anserina aggregates completely inhibited the appearance of SDS-resistant oligomers. This combination of HTP in vitro screening with validation in fungi models provides an efficient way to identify novel inhibitory compounds of Aβ1–42 aggregation for subsequent testing in animal models.