TRPV Pharmacophores from Cnidaria Venom

刺胞动物毒液 TRPV 药效团

• 批准号: 7628403
• 负责人: ANGEL ANNE YANAGIHARA
• 金额: $ 20.6万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7628403
• 关键词: Afferent Neurons; Agonist; Amines; Analgesics; Anti Inflammatory Analgesics; Biochemical; Biological Assay; Biological Availability; Biological Factors; Boxing; Cannabinoids; Carybdea; Cations; Chemical Structure; Chemicals; Chronic; Clinical; Cnidaria; Cnidarian Venoms; Complex; Data; Detection; Development; Eligibility Determination; Evaluation; Family; Fishes; Fractionation; Freezing; Future; G Protein-Coupled Receptor Genes; Goals; Hawaiian population; High Pressure Liquid Chromatography; Human; Inflammation; Inflammatory; Inflammatory Response; Lead; Ligands; Lipids; Liquid substance; Mass Fragmentography; Mass Spectrum Analysis; Mediating; Methodology; Methods; Molecular; NMR Spectroscopy; Neurogenic Inflammation; Neurons; Nitrogen; Nociception; Nuclear Magnetic Resonance; Operative Surgical Procedures; Organ; Outcome; Pain; Peripheral; Pharmacology; Property; Proteins; Reporting; Research; Research Project Grants; Research Proposals; Respiratory Failure; Risk; Role; Screening procedure; Sonication; Source; Spectroscopy, Fourier Transform Infrared; Sting Injury; Structure; System; TRPV channel; TRPV1 gene; Techniques; Testing; Therapeutic; Therapeutic Agents; Therapeutic Studies; Tissues; Venoms; Visceral; Work; aqueous; base; capsule; cell type; cross reactivity; drug discovery; evaporation; high risk; human tissue; insight; intense pain; nervous system disorder; novel; pharmacophore; research study; response; sensor; small molecule

TRPV cation channels have been ascribed roles in nocioception and the induction of neurogenic inflammation. We hypothesized that the intense pain and constellation of neuro-inflammatory effects following cnidarian envenomation in humans are mediated by TRPV channel-sensors, and that cnidarian venoms contain novel components that are active on TRPV channels. Recently, we have demonstrated TRPV1 activity in tentacle extracts of all major classes of Cnidaria. Since TRPV cation channels have been ascribed roles in nocioception and the induction of neurogenic inflammation, we hypothesized that certain effects of cnidarian envenomation are mediated by TRPV channel-sensors and that cnidarian venoms contain novel neuroactive and immunoactive pharmacophores which are active at TRPVs. Another compelling argument in favor of a role for TRPVs in cnidarian envenomation is the marked chemical conservation between known ligands for TRPVs and components of cnidarian venoms. This revised exploratory research proposal, submitted in response to PAR-07-048 (Drug Discovery for Nervous System Disorders), seeks to identify and characterize novel pharmacophores that target TRPV cation channels in the venom of the cnidarian, Carybdea alata. Our experimental plan employs bioassay-directed fractionation methods, and combined spectroscopic approaches for the detection, purification and characterization of newfound TRPV1 pharmacophores. Specific Aim 1. Screen for TRPV-active compounds in C. alata venom. Low- to medium-throughput screening protocols, which integrate novel biochemical and conventional electrophysiological TRPV assays, will be employed to identify TRPV1 agonists in C. alata venom. Specific Aim 2. Purify and characterize TRPV pharmacophores from C. alata venom. These early metazoan TRPV pharmacophores will be isolated using paired biochemical purification/bioassay techniques and characterized by high-performance liquid chromatography (HPLC), gas chromatography (GC), and mass spectrometry (MS), and nuclear magnetic resonance (NMR) spectroscopy. Our focus on the cnidarian system minimizes the inherent risk in this type of natural product discovery effort. That is, the outcome from probing these ancient metazoans for novel structures with TRPV1 activity will not simply recapitulate previously reported bioactive compounds. The dual impact of this work will be to provide much-needed, novel pharmacology for TRPV channels, and to gain mechanistic insights into the pathological effects of cnidarian venoms. In view of recent advances which demonstrate the marked therapeutic potential of TRPV1 agonists, as well as antagonists, in the treatment of pain associated with chronic inflammation and surgery, the potential therapeutic utility of novel TRPV1 pharmacophores from cnidaria is extremely high. TRPV proteins are targets for the development of new pain medications. The venom of the Hawaiian box jelly fish contains potentially novel compounds which target TRPV channels. We will explore the chemical diversity of this venom to discover new lead compounds for the management of neurological disorders.

TRPV阳离子通道已在Nocioception和神经源性炎症的诱导中赋予了作用。 我们假设Cnidarian后神经炎症效应的剧烈疼痛和星座 人类的浓度是由TRPV频道传感器介导的，而Cnidarian毒液包含新颖 在TRPV通道上活跃的组件。最近，我们在触手中展示了TRPV1活动 所有主要类Cnidaria的提取物。由于TRPV阳离子通道已归因于 Nocioception和神经源性炎症的诱导，我们假设Cnidarian的某些影响 衰弱是由TRPV通道传感器介导的，并且cnidarian毒液含有新型神经活​​性 和在TRPV处活跃的免疫活性药理。另一个令人信服的论点赞成角色 对于cnidarian的TRPV，毒化是已知的TRPV配体之间的明显化学保守 和Cnidarian毒液的成分。这项修订的探索性研究提案，响应于 PAR-07-048（神经系统疾病的药物发现）试图识别和表征新颖的 靶向TRPV阳离子通道的药物团在Cnidarian Carybdea Alata的毒液中。我们的 实验计划采用生物测定指导的分级方法，并结合了光谱方法 为了检测，新发现的TRPV1药体的纯化和表征。 特定的目标1。在毒液中，TRPV活性化合物的筛选。 低到中等通量筛选方案，该方案整合了新型生化和常规的筛选方案 电生理TRPV测定法将用于鉴定C. alata毒液中的TRPV1激动剂。 具体目标2。纯化和表征来自C. alata毒液的TRPV药算术。 这些早期的后代TRPV药理将使用成对的生化纯化/生化分离 技术和以高性能液相色谱法（HPLC），气相色谱法（GC）的特征 和质谱（MS）以及核磁共振（NMR）光谱。 我们对Cnidarian系统的关注使这种天然产品发现工作中的固有风险最小化。 也就是说，探测这些古老的后生动物的结果 简单地概括了先前报道的生物活性化合物。这项工作的双重影响是提供 急需的TRPV通道的新型药理学，并获得对病理的机械见解 毒液的作用。鉴于最近的进步证明了明显的治疗潜力 TRPV1激动剂以及拮抗剂，以治疗与慢性炎症相关的疼痛和 手术，来自Cnidaria的新型TRPV1药算术的潜在治疗效用非常高。 TRPV蛋白是开发新止痛药的靶标。夏威夷盒果冻的毒液 鱼含有靶向TRPV通道的潜在新颖化合物。我们将探索化学多样性 该毒液发现用于管理神经系统疾病的新铅化合物。