Discovery of Novel Inhibitors of Amyloid 尾-Peptide 1鈥?2 Aggregation

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• 作者：Laura C. L贸pez ; Suzana Dos-Reis ; Alba Espargar贸 ; Jos茅 A. Carrodeguas ; Marie-Lise Maddelein ; Salvador Ventura ; Javier Sancho
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：9521-9530
• 全文大小：483K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

Alzheimer's disease, characterized by deposits of amyloid 尾-peptide (A尾), 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 A尾17鈥?0 peptide by screening two commercial chemical libraries. Four of them (1鈥?b>4) exhibit relatively low MCCs toward HeLa cells (17鈥?84 渭M). The usefulness of compounds 1鈥?b>4 to inhibit the in vivo aggregation of A尾1鈥?2 has been demonstrated using two fungi models, Saccharomyces cerevisiae and Podospora anserina, previously transformed to express A尾1鈥?2. Estimated IC₅₀s are around 1鈥? 渭M. 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 A尾1鈥?2 aggregation for subsequent testing in animal models.