Glycosaminoglycan-Interacting Small Molecule (GISMO) as Parkinson's Therapeutic

糖胺聚糖相互作用小分子（GISMO）作为帕金森病治疗剂 摘要 目前批准的帕金森病（PD）药物治疗疾病的症状，但 而不是阻止疾病的发展。该项目的重点是开发一种新的疾病修饰 PD治疗剂具有预期可阻断疾病进展的新型作用模式。 最近的数据表明，硫酸乙酰肝素糖胺聚糖（HS-GAG）是受体 负责α-突触核蛋白蛋白质病种子的内化和传播， CNS。我们认为，抑制HS-GAG介导的内化可以实现 通过干扰α-突触核蛋白和HS-GAG之间的相互作用， 这种相互作用将导致鉴定用于PD和其他突触核蛋白病的新治疗。 我们以前已经表明，糖胺聚糖相互作用小分子（GISMO）是一种 新的、结构多样的化合物，其在体外和体内具有生物活性， 我们的目标是靶向HS-GAG介导的α-突触核蛋白的内化和聚集 蛋白质疗法种子和GISMO在这个项目的前期工作中，我们筛选了一个 在96孔板上使用新的α-突触核蛋白- HS-GAG相互作用测定的GISMO样化合物 平板筛选，鉴定出15个目标化合物（抑制活性>30%）， 进一步发展。在拟议的项目中，我们将首先筛选15种热门化合物， 抑制神经元细胞中的α-突触核蛋白内化和细胞毒性作用。GISMO 预期化合物抑制HS-GAG介导的α-突触核蛋白摄取。铅系列 然后，将具有可接受的体外功效、选择性和安全性的化合物进行 通过药物化学进行化学优化。选择的4-5种先导化合物将 通过药代动力学评价口服生物利用度和脑渗透性质。三 随后将在帕金森病的动物模型中测试所选择的先导化合物， 与PatrikBrundin博士（大急流城，货车Andel研究所， MI）。这些研究的成功完成将有助于确定临床前候选药物 进行IND赋能研究。开发一种改善疾病的治疗方法将是 帕金森氏病治疗的最重要的进展，因为发展 左旋多巴在20世纪60年代

Glycosaminoglycan-Interacting Small Molecule (GISMO) As Parkinson's Therapeutics ABSTRACT Current approved drugs for Parkinson's Disease (PD) treat the symptoms of the disease but do not stop disease progression. This project is focused on developing a new disease-modifying PD therapeutic with a novel mode of action that is expected to block disease progression. Recent data indicate that heparan sulfate glycosaminoglycans (HS-GAGs) are the receptors responsible for internalization and spreading of alpha-synuclein proteopathic seeds across the CNS. We propose that the inhibition of the HS-GAG-mediated internalization can be achieved by interfering with the interaction between alpha-synuclein and HS-GAGs, and that targeting this interaction will lead to the identification of new treatments for PD and other synucleinopathies. We have previously shown that Glycosaminoglycan-Interacting Small Molecule (GISMO) are a new, structurally-diverse class of compounds that are biologically active in vitro and in vivo and we aim to target the HS-GAG – mediated internalization and aggregation of alpha-synuclein proteopathic seeds with GISMOs. In preliminary work for this project, we screened a library of GISMO-like compounds using a new alpha-synuclein - HS-GAG interaction assay on 96-well plates and identified 15 hit compounds (with inhibitory activity >30%), that have been selected for further development. In the proposed project, we will first screen the 15 hit compounds for inhibition of alpha-synuclein internalization in neuronal cells, and cytotoxic effects. GISMO compounds are expected to inhibit HS-GAG-mediated alpha-synuclein uptake. Lead series of compounds with acceptable efficacy, selectivity and safety in vitro will be then subjected to chemical optimization via medicinal chemistry. The selected 4-5 lead compounds will be evaluated by pharmacokinetics, for oral bioavailability and brain-penetrant properties. Three chosen lead compounds will be subsequently tested in an animal model of Parkinson's Disease, in collaboration with team of Dr. Patrik Brundin (Van Andel Research Institute, Grand Rapids, MI). The successful completion of these studies will enable identifying a Preclinical Candidate for IND-enabling studies. The development of a disease-modifying therapeutic would be the most significant advancement in Parkinson’s disease therapeutics since the development of levodopa in the 1960s.