Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
J Phys Chem B. 2023 Mar 9;127(9):1983-1994. doi: 10.1021/acs.jpcb.3c00280. Epub 2023 Feb 27.
GV-971 (sodium oligomannate) is a China Food and Drug Administration (CFDA)-approved drug for treating Alzheimer's disease, and it could inhibit Aβ fibril formation in vitro and in mouse studies. To elucidate the mechanisms for understanding how GV-971 modulates Aβ's aggregation, we conducted a systematic biochemical and biophysical study of Aβ40/Aβ42:GV-971 systems. The integrating analysis of previously published data and our results suggests that the multisite electrostatic interactions between GV-971's carboxylic groups and Aβ40/Aβ42's three histidine residues might play a dominant role in driving the binding of GV-971 to Aβ. The fuzzy-type electrostatic interactions between GV-971 and Aβ are expected to protect Aβ from aggregation potentially through breaking the histidine-mediated inter-Aβ electrostatic interactions. Meanwhile, since GV-971's binding exhibited a slight downregulation effect on the flexibility of Aβ's histidine-colonized fragment, which potentially favors Aβ aggregation, we conclude that the dynamics alteration plays a minor role in GV-971's modulation on Aβ aggregation.
GV-971（寡甘露糖醛酸）是中国食品药品监督管理局（CFDA）批准用于治疗阿尔茨海默病的药物，它可以抑制体外和小鼠研究中的 Aβ 纤维形成。为了阐明理解 GV-971 如何调节 Aβ 聚集的机制，我们对 Aβ40/Aβ42:GV-971 系统进行了系统的生化和生物物理研究。对先前发表的数据和我们的结果进行综合分析表明，GV-971 的羧酸基团与 Aβ40/Aβ42 的三个组氨酸残基之间的多点静电相互作用可能在驱动 GV-971 与 Aβ 的结合中起主导作用。GV-971 与 Aβ 之间的模糊型静电相互作用有望通过破坏组氨酸介导的 Aβ 间静电相互作用来保护 Aβ 免受聚集。同时，由于 GV-971 的结合对 Aβ 组氨酸定植片段的灵活性表现出轻微的下调作用，这可能有利于 Aβ 聚集，因此我们得出结论，动力学变化在 GV-971 对 Aβ 聚集的调节中作用较小。
