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

糖胺聚糖相互作用小分子 (GISMO) 作为帕金森病的治疗药物

• 批准号: 9321231
• 负责人: Paul Gregor
• 金额: $ 14.22万
• 依托单位: GISMO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321231
• 关键词: Amyloid; Animal Model; Binding; Bioavailable; Biological; Biological Assay; Biological Availability; Brain; Brain region; C57BL/6 Mouse; Cell Culture Techniques; Cell Death; Cell Surface Receptors; Cell surface; Cells; Characteristics; Chemicals; Collaborations; Complex; Data; Development; Disease; Disease Progression; Drug Kinetics; Evaluation; GAG Gene; Glycosaminoglycans; Goals; Heparitin Sulfate; Hippocampus (Brain); Human; Immunohistochemistry; In Vitro; Injection of therapeutic agent; Investigation; Label; Lead; Levodopa; Libraries; Measures; Mediating; Nerve Degeneration; Neurons; Oral; Parkinson Disease; Patients; Pattern; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacy (field); Plasma; Property; Proteins; Reporting; Research Institute; Rodent; Safety; Seeds; Series; Solubility; Testing; Therapeutic; Toxic effect; Toxicology; Work; acute toxicity; alpha synuclein; analog; base; cytotoxic; cytotoxicity; efficacy study; experimental study; glycosaminoglycan receptor; improved; in vitro Assay; in vivo; inhibitor/antagonist; lead series; motor impairment; mouse model; neuroblastoma cell; neuroprotection; novel; novel therapeutics; olfactory bulb; phase 1 study; polysulfated glycosaminoglycan; pre-clinical; preclinical safety; prevent; programs; reduce symptoms; screening; small molecule; small molecule inhibitor; symptom treatment; synucleinopathy; uptake

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.

糖胺多糖相互作用小分子(GISMO)作为帕金森病的治疗药物 摘要 目前批准的治疗帕金森氏病(PD)的药物可以治疗该病的症状，但确实 而不是阻止疾病的发展。本项目致力于开发一种新的疾病改良剂 帕金森病的治疗具有一种新的作用模式，有望阻止疾病的进展。 最近的数据表明，硫酸乙酰肝素糖胺多聚糖(HS-GAG)是受体 负责α-突触核蛋白蛋白种子的内化和传播 中枢神经系统。我们认为抑制HS-GAG介导的内化是可以实现的 通过干扰α-突触核蛋白和HS-GAG之间的相互作用，以及靶向于此 相互作用将导致确定帕金森病和其他联体核病的新治疗方法。 我们以前已经证明，糖胺聚糖相互作用的小分子(Gismo)是一种 一类新的、结构多样化的化合物，在体外和体内都具有生物活性 我们的目标是针对HS-GAG介导的α-突触核蛋白的内化和聚集 具Gismos的多面体种子。在这个项目的前期工作中，我们筛选了一个 用新的α-突触核蛋白-HS-GAG相互作用分析96孔道上的类Gismo化合物 并鉴定了15个热门化合物(具有抑制活性&gt；30%)。 为了进一步的发展。在建议的项目中，我们将首先筛选出15种热门化合物 抑制α-突触核蛋白在神经细胞中的内化，以及细胞毒效应。Gismo 化合物有望抑制HS-GAG介导的α-突触核蛋白摄取。铅系列 在体外具有可接受的有效性、选择性和安全性的化合物将接受 通过药物化学进行化学优化。选定的4-5个先导化合物将是 通过药代动力学评价口服生物利用度和脑渗透特性。三 选定的先导化合物随后将在帕金森氏病的动物模型中进行测试， 与Patrik Brundin博士(Van Andel研究所，Grand Rapids， MI)。这些研究的成功完成将使确定临床前候选人成为可能 用于支持IND的研究。一种治疗疾病的疗法的开发将是 帕金森氏病治疗的最重大进展 左旋多巴在20世纪60年代。