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

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 IC(50)s 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.

Multitarget trehalose-carnosine conjugates inhibit Aβ aggregation, tune copper(II) activity and decrease acrolein toxicity

“…Indeed, it has been reported that drugs able to prevent the oligomerization and fibrillation processes of Aβ are of high therapeutic value in AD treatment. [43] Thus, the ability of Tr-linked Car as well as their parent compounds to inhibit Aβ 1-42 self-induced fibrillar aggregation was tested by using a thioflavin-T (ThT) based fluorimetric assay. The most relevant kinetic parameters are listed in Table 1.…”

Application of Yeast to Study the Tau and Amyloid-β Abnormalities of Alzheimer's Disease

“…The authors also show that after screening 5,000 genes with the aim of finding A␤ toxicity modifiers, they have identified 12 with human homologs, further implicating the benefit of yeast models in the genome-wide association studies. In a similar way, López and colleagues after screening two commercial chemical libraries have identified four compounds capable of inhibiting A␤ aggregation in S. cerevisiae and Podospora anserine [58].…”

Inhibitors of protein aggregates as novel drugs in neurodegenerative diseases

“…This region, known as the KLVFFA, is an hexapeptide sequence that facilitates monomer-monomer interaction, leading to dimer and oligomer formation [48,49]. Based on these findings, a few compounds have been identified and demonstrated to interact with the KLVFFA region [50].…”