Galimedix Therapeutics Inc., 2704 Calvend Lane, Kensington, MD 20895, USA.
Laboratory of Cellular and Molecular Physiology, Department of Biosciences, University of Milano, Via Celoria 26, 20133 Milano, Italy.
Int J Mol Sci. 2022 May 21;23(10):5794. doi: 10.3390/ijms23105794.
Soluble amyloid β (Aβ) oligomers have been shown to be highly toxic to neurons and are considered to be a major cause of the neurodegeneration underlying Alzheimer's disease (AD). That makes soluble Aβ oligomers a promising drug target. In addition to eliminating these toxic species from the patients' brain with antibody-based drugs, a new class of drugs is emerging, namely Aβ aggregation inhibitors or modulators, which aim to stop the formation of toxic Aβ oligomers at the source. Here, pharmacological data of the novel Aβ aggregation modulator GAL-201 are presented. This small molecule (288.34 g/mol) exhibits high binding affinity to misfolded Aβ monomers (K = 2.5 ± 0.6 nM). Pharmacokinetic studies in rats using brain microdialysis are supportive of its oral bioavailability. The Aβ oligomer detoxifying potential of GAL-201 has been demonstrated by means of single cell recordings in isolated hippocampal neurons (perforated patch experiments) as well as in vitro and in vivo extracellular monitoring of long-term potentiation (LTP, in rat transverse hippocampal slices), a cellular correlate for synaptic plasticity. Upon preincubation, GAL-201 efficiently prevented the detrimental effect on LTP mediated by Aβ oligomers. Furthermore, the potential to completely reverse an already established neurotoxic process could also be demonstrated. Of particular note in this context is the self-propagating detoxification potential of GAL-201, leading to a neutralization of Aβ oligomer toxicity even if GAL-201 has been stepwise removed from the medium (serial dilution), likely due to prion-like conformational changes in Aβ monomer aggregates (trigger effect). The authors conclude that the data presented strongly support the further development of GAL-201 as a novel, orally available AD treatment with potentially superior clinical profile.
可溶性淀粉样β（Aβ）寡聚体已被证明对神经元具有高度毒性，被认为是阿尔茨海默病（AD）神经退行性变的主要原因。这使得可溶性 Aβ 寡聚体成为有前途的药物靶点。除了用基于抗体的药物从患者大脑中清除这些毒性物质外，还出现了一类新的药物，即 Aβ 聚集抑制剂或调节剂，其目的是从源头上阻止有毒 Aβ 寡聚体的形成。这里介绍了新型 Aβ 聚集调节剂 GAL-201 的药理学数据。这种小分子（288.34 g/mol）对错误折叠的 Aβ 单体具有高结合亲和力（K = 2.5 ± 0.6 nM）。使用脑微透析进行的大鼠药代动力学研究支持其口服生物利用度。通过在分离的海马神经元（穿孔贴片实验）中进行单细胞记录以及在体外和体内监测长时程增强（LTP，在大鼠横海马切片中），GAL-201 已被证明具有 Aβ 寡聚体解毒潜力，这是突触可塑性的细胞相关性。孵育前，GAL-201 可有效防止 Aβ 寡聚体对 LTP 的有害影响。此外，还证明了完全逆转已经建立的神经毒性过程的潜力。在这方面特别值得注意的是 GAL-201 的自我传播解毒潜力，即使 GAL-201 已逐步从培养基中去除（连续稀释），也能导致 Aβ 寡聚体毒性的中和，这可能是由于 Aβ 单体聚集的类朊病毒构象变化（触发效应）。作者得出结论，所提供的数据强烈支持进一步开发 GAL-201 作为一种新型的、可口服的 AD 治疗药物，具有潜在的优越临床特征。
