Discovery of novel inhibitors of amyloid β-peptide 1-42 aggregation

Laura C. López, Suzana Dos-Reis, Alba Espargaró, José A. Carrodeguas, Marie Lise Maddelein, Salvador Ventura, Javier Sancho

Research output: Contribution to journalArticleResearchpeer-review

39 Citations (Scopus)

Abstract

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. © 2012 American Chemical Society.
Original languageEnglish
Pages (from-to)9521-9530
JournalJournal of Medicinal Chemistry
Volume55
Issue number22
DOIs
Publication statusPublished - 26 Nov 2012

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