1 research outputs found
Design of β-Amyloid Aggregation Inhibitors from a Predicted Structural Motif
Drug design studies targeting one of the primary toxic
agents in Alzheimer’s disease, soluble oligomers of amyloid
β-protein (Aβ), have been complicated by the rapid, heterogeneous
aggregation of Aβ and the resulting difficulty to structurally
characterize the peptide. To address this, we have developed [Nle<sup>35</sup>, d-Pro<sup>37</sup>]ÂAβ<sub>42</sub>, a substituted
peptide inspired from molecular dynamics simulations which forms structures
stable enough to be analyzed by NMR. We report herein that [Nle<sup>35</sup>, d-Pro<sup>37</sup>]ÂAβ<sub>42</sub> stabilizes
the trimer and prevents mature fibril and β-sheet formation.
Further, [Nle<sup>35</sup>, d-Pro<sup>37</sup>]ÂAβ<sub>42</sub> interacts with WT Aβ<sub>42</sub> and reduces aggregation
levels and fibril formation in mixtures. Using ligand-based drug design
based on [Nle<sup>35</sup>, d-Pro<sup>37</sup>]ÂAβ<sub>42</sub>, a lead compound was identified with effects on inhibition
similar to the peptide. The ability of [Nle<sup>35</sup>, d-Pro<sup>37</sup>]ÂAβ<sub>42</sub> and the compound to inhibit
the aggregation of Aβ<sub>42</sub> provides a novel tool to
study the structure of Aβ oligomers. More broadly, our data
demonstrate how molecular dynamics simulation can guide experiment
for further research into AD