Isolation and identification of CXCR4 and CXCR7 agonists from traditional phytopharmaceuticals as potential novel drugs for mental disorders

从传统植物药物中分离鉴定 CXCR4 和 CXCR7 激动剂作为治疗精神障碍的潜在新药

• 批准号: 10054069
• 负责人: Abraham Jaime Vaisberg
• 金额: $ 13.4万
• 依托单位: UNIVERSIDAD PERUANA CAYETANO HEREDIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054069
• 关键词: ARNT gene; Adherence; Affect; Agonist; Animal Model; Anti-Anxiety Agents; Antidepressive Agents; Antipsychotic Agents; Anxiety; Behavior; Biological Assay; Biological Process; Biology; Blood Circulation; Blood Vessels; Botanicals; Brain; CXC Chemokines; CXCL12 gene; CXCR4 Receptors; CXCR4 gene; Cardiotoxicity; Chemicals; Collaborations; Collection; Complex; Data; Dementia; Development; Diffusion; Disease; Dose; Drug Targeting; Endothelial Cells; Ethanol; Exhibits; Family; Fractionation; Funding; G-Protein-Coupled Receptors; Genes; Geographic Locations; Goals; Immune response; Immune system; Inflammation; Institution; International; Intervention; Knockout Mice; Knowledge; Lead; Ligands; Mental disorders; Molecular; Molecular Structure; National Institute of Mental Health; Nervous system structure; Neural Pathways; Neuroglia; Neurons; Neurophysiology - biologic function; Neurosecretory Systems; North Carolina; Olfactory Epithelium; Outcome; Pathologic; Pathologic Processes; Patients; Peru; Peruvian; Pharmacology; Physiological; Physiological Processes; Plants; Pregnancy; Prevention; Production; Psychotropic Drugs; Rattus; Research; Role; Sampling; Schizophrenia; Site; Source; Strategic Planning; Stromal Cell-Derived Factor 1; Structure-Activity Relationship; Students; Testing; Therapeutic; Traditional Medicine; Training; Transportation; United States National Institutes of Health; Universities; Work; alcohol testing; angiogenesis; autism spectrum disorder; base; behavioral phenotyping; beta-arrestin; chemokine; chemokine receptor; disabling disease; drug discovery; first episode schizophrenia; follow-up; improved; interest; international center; lectures; member; neurodevelopment; neurogenesis; neurotoxicity; new therapeutic target; novel; novel therapeutics; offspring; receptor; repository; response; screening program; sedative; stereotypy; symposium; therapeutic target; trait; white matter

7. Project Summary/Abstract. We aim to take advantage of traditional medicine knowledge to direct the discovery of novel therapeutics for mental disorders that will eventually help to unravel yet poorly understood biological processes behind the occurrence of these diseases. Previous studies have led us to collect information on the use of plants for treating mental disorders in several Peruvian localities and geographical regions. We have a repository of ethanol extracts from 477 plant collections corresponding to 265 species from 87 different plant families. These plants have been used for centuries for one or more of the following activities: antipsychotic, antidepressant, anxiolytic and sedative. The overall long-term aim inherent to this proposal is to identify molecular pathways of neural function that are promising new intervention targets for mental disorders. For this specific R21 we aim to isolate novel neuroactive compounds acting on the chemokine G- protein coupled receptors (GPCRs) CXCR4 and CXCR7. The proposed work will have the support of the NIMH Psychoactive Drug Screening Program (PDSP) (a) to aid in the bioassays for the guided fractionation of the raw extracts we have in our repository and (b) to further consolidate an independent research platform for the study of these specific novel drug targets, based in our institution. Working in collaboration with the PDSP we have been able to identify 58 extracts from our repository which showed potential agonist activity for CXCR4 and CXCR7 receptors in a primary functional screen. From them, 3 extracts show dose-dependent response curves for both CXCR4 and CXCR7, and 12 for CXCR7 alone. CXCR4 and CXCR7 act as receptors for the CXC chemokine ligand 12, CXCL12 (also called SDF-1 alpha). Evidence supports their role in the interaction between the nervous and immune systems. The involvement of CXCR4 and CXCR7 in mental disorders has started to be discussed only in the past few years. Our data, showing that botanicals used for treating mental disorders contain agonists for these receptors support this possible role. An additional challenge is that there is a lack of pharmacologically active compounds identified or developed for these targets. GPCRs participate in diverse physiological functions and are promising targets for drug discovery. For this reason, the elucidation of their biological function is compelling. Our specific aims are: To perform bioassay-guided fractionation of the 15 extracts active at CXCR4 or CXCR7, to dereplicate and determine the molecular structure of the isolated active compound(s), and to provide outstanding students located in Peru the opportunity to do their thesis work, present their results at major international conferences, and to train on drug discovery research approaches.

7.项目概要/摘要。我们的目标是利用传统医学知识指导 发现新的治疗精神疾病的方法，最终将有助于解开但知之甚少的 这些疾病发生背后的生物学过程。之前的研究让我们收集信息 在秘鲁的几个地方和地理区域使用植物治疗精神疾病。我们 拥有来自477种植物收藏的乙醇提取物储存库，对应于来自87个不同的265个物种 植物家族几个世纪以来，这些植物一直用于以下一种或多种活动： 抗精神病药、抗抑郁药、抗焦虑药和镇静剂。这一建议的总体长期目标是 识别神经功能的分子途径，这些分子途径是有希望的精神疾病的新干预靶点。 紊乱对于这种特定的R21，我们的目标是分离新的神经活性化合物作用于趋化因子G- 蛋白偶联受体（GPCR）CXCR 4和CXCR 7。拟议的工作将得到NIMH的支持 精神活性药物筛选计划（PDSP）（a）协助进行生物测定，以指导原料药的分馏 提取我们在我们的知识库和（B）进一步巩固一个独立的研究平台， 研究这些特定的新药靶点，基于我们的机构。 与PDSP合作，我们已经能够从我们的存储库中识别出58个摘录， 在初步功能筛选中显示出对CXCR 4和CXCR 7受体的潜在激动剂活性。从他们那里， 3种浸提液显示CXCR 4和CXCR 7的剂量依赖性反应曲线，12种浸提液显示CXCR 7单独的剂量依赖性反应曲线。 CXCR 4和CXCR 7作为CXC趋化因子配体12，CXCL 12（也称为SDF-1 α）的受体。 证据支持它们在神经和免疫系统之间的相互作用中的作用。的参与 CXCR 4和CXCR 7在精神疾病中的作用只是在过去几年才开始讨论。我们的数据， 这表明用于治疗精神障碍的植物药含有这些受体的激动剂， 可能的角色。另一个挑战是缺乏已鉴定的抗肿瘤活性化合物 或针对这些目标开发的。GPCR参与多种生理功能，是有希望的靶点 用于药物研发。因此，对它们的生物学功能的阐明是令人信服的。 我们的具体目标是：对CXCR 4或CXCR 7活性的15种提取物进行生物测定指导的分级分离， 去复制和确定分离的活性化合物的分子结构，并提供 位于秘鲁的优秀学生有机会做他们的论文工作，介绍他们的主要成果 国际会议，并就药物发现研究方法进行培训。