Investigation of Methylsulfonamide’s Capability to Prevent Zn2+-Induced Aβ Peptide Aggregation Based on Zn2+ Coordination within the Zinc Binding Region of Aβ for Treatment of Alzheimer’s Disease (AD)

There is no cure for Alzheimer's disease (AD) with the currently suggested therapies. Thus, designing and synthesis of new drugs for the treatment of Alzheimer's disease for safe and effective therapy have become an important task. Metal ions such as Zn²⁺, Cu²⁺, and Fe³⁺ are known to increase the rate of Aβ aggregation and exist in amyloid plaques at high concentrations. Aβ oligomers, whether formed on the way to amyloid fibril formation or formed off-pathway due to the interaction of Aβ monomers with Zn²⁺, are considered to be the most neurotoxic aggregates. Using NMR and SPR, this study reports the methylsulfonamide inhibition of Zn²⁺-induced Aβ_1-16 dimer formation via methylsulfonamide coordination of Zn²⁺ within the Zn²⁺ binding region of Aβ, (₁₁EVHH₁₄) and inhibit the H14-Zn²⁺ coordination between the ₁₁EVHH₁₄ regions of two Aβ peptides, preventing their interactions and hence the Aβ dimer formation. According to the results of this study, methylsulfonamide has the potential to be used as a drug in Alzheimer's disease for the prevention of the formation of the Zn²⁺-induced toxic Aβ oligomers formed during Aβ aggregation.