Ataman Sadık Demet, Cansız Cemre Sare, Turğut Merve, Dağ Çağdaş, Duman Memed
Institute of Natural and Applied Sciences, Division of Nanotechnology and Nanomedicine, Hacettepe University, 06800 Ankara, Turkey.
Nanofabrication and Nanocharacterization Center for Scientific and Technological Advanced Research (n2STAR), Koç University, 34450 Istanbul, Turkey.
ACS Chem Neurosci. 2025 Aug 6;16(15):2945-2957. doi: 10.1021/acschemneuro.5c00238. Epub 2025 Jul 23.
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 Zn, Cu, and Fe 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 Zn, are considered to be the most neurotoxic aggregates. Using NMR and SPR, this study reports the methylsulfonamide inhibition of Zn-induced Aβ dimer formation via methylsulfonamide coordination of Zn within the Zn binding region of Aβ, (EVHH) and inhibit the H14-Zn coordination between the EVHH 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 Zn-induced toxic Aβ oligomers formed during Aβ aggregation.
目前推荐的治疗方法无法治愈阿尔茨海默病（AD）。因此，设计和合成用于治疗阿尔茨海默病的新药以实现安全有效的治疗已成为一项重要任务。已知锌、铜和铁等金属离子会增加Aβ聚集的速率，并以高浓度存在于淀粉样斑块中。Aβ寡聚体，无论是在淀粉样原纤维形成过程中形成的，还是由于Aβ单体与锌的相互作用在非途径中形成的，都被认为是最具神经毒性的聚集体。本研究利用核磁共振（NMR）和表面等离子体共振（SPR）报告了甲磺酰胺通过在Aβ的锌结合区域（EVHH）内与锌配位来抑制锌诱导的Aβ二聚体形成，并抑制两个Aβ肽的EVHH区域之间的H14-Zn配位，从而阻止它们的相互作用以及Aβ二聚体的形成。根据本研究结果，甲磺酰胺有潜力作为一种药物用于阿尔茨海默病，以预防在Aβ聚集过程中形成的锌诱导的有毒Aβ寡聚体。
