Pseudopeptide Amyloid Aggregation Inhibitors: In Silico, Single Molecule and Cell Viability Studies.

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Alzheimer's disease (AD) neurodegeneration involves amyloid-beta (Aβ) aggregation into toxic oligomers.
• Preventing Aβ oligomer formation is a therapeutic strategy for AD.
• SG inhibitors are pseudopeptides designed to inhibit Aβ aggregation.

Purpose of the Study:

• To review previous molecular dynamics (MD) and single molecule force spectroscopy (SMFS) studies of SG inhibitors.
• To evaluate the neuroprotective effects of SG inhibitors against Aβ(1-42) oligomers in HT22 cells.
• To assess the impact of myristoylation on SG inhibitor efficacy and toxicity.

Main Methods:

• Molecular dynamics (MD) simulations for inhibitor design and optimization.
• Single molecule force spectroscopy (SMFS) for experimental validation of Aβ binding inhibition.
• Cell viability assays using mouse hippocampal-derived HT22 cells to assess neuroprotection against Aβ(1-42) oligomers.

Main Results:

• Two SG inhibitors, predicted to bind Aβ in an anti-parallel orientation, demonstrated neuroprotection against Aβ(1-42) oligomers.
• A third SG inhibitor, predicted to bind parallel to Aβ, did not show neuroprotective effects.
• Myristoylation of SG inhibitors led to cytotoxicity, despite enhancing blood-brain barrier (BBB) penetration potential.

Conclusions:

• SG inhibitors targeting Aβ aggregation show promise for Alzheimer's disease treatment.
• Inhibitor binding orientation influences neuroprotective efficacy.
• Myristoylation for BBB penetration requires further optimization to avoid cytotoxicity.