ConoPeptides - G-Protein Coupled Receptors

ConoPeptides - G 蛋白偶联受体

• 批准号: 8145708
• 负责人: GRZEGORZ BULAJ
• 金额: $ 19.47万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8145708
• 关键词: Absence of pain sensation; Accounting; Affinity; Agonist; Analgesics; Applications Grants; Arts; Biochemical; Biological Assay; Bolus Infusion; Brain; C-terminal; Carbohydrates; Characteristics; Chimera organism; Clinical; Clinical Trials; Competitive Binding; Conotoxin; Continuous Infusion; Conus Venom; Conus genus; Detection; Development; Dose; Drug Delivery Systems; Europium; FDA approved; Family; Fluorescence; Formalin; Future; G-Protein-Coupled Receptors; Gene Family; Glycopeptides; Goals; Half-Life; Human; In Vitro; Inhibitory Concentration 50; Injection of therapeutic agent; Label; Lead; Libraries; Manuals; Mediating; Membrane; Metabolic; Methods; Modeling; Molecular; Molecular Biology; N-terminal; NMR Spectroscopy; Neuropeptides; Neurotensin; Neurotensin Receptors; Oocytes; Outcome; Peptide Synthesis; Peptides; Phase; Post-Translational Protein Processing; Preparation; Program Development; Property; Proteins; Rattus; Receptor Activation; Research; Research Proposals; Snail Venoms; Solid; Solutions; Source; Spinal cord injury patients; Structure; Structure-Activity Relationship; Technology; Testing; Therapeutic; Time; analog; animal pain; base; chemical synthesis; desensitization; design; experience; glycosylation; member; nervous system disorder; novel; novel strategies; overexpression; painful neuropathy; prevent; programs; receptor; release of sequestered calcium ion into cytoplasm; therapeutic target

The long-term goal of this project is to characterize structural, biochemical and pharmacological properties of conopeptides that target G-protein coupled receptors (GPCRs). In the proposed research, we will focus on studying structure-activity-relationships of a unique analgesic conopeptide, Contulakin-G, targeting neurotensin receptors (NTRs). Contulakin-G is a 16-residue peptide isolated from venom of Conus geographus. This peptide shares the C-terminal sequence similarity with an endogenous neuropeptide, neurotensin (NT), but it also contains an unusual posttranslational modification: O-glycosylation of a Thr residue. A unique pharmacological property of Contulakin-G is that this very potent analgesic compound is a low-affinity, non-desensetizing agonist for neurotensin receptors. In stark contrast to Contulakin-G, NT is 600-fold less potent as analgesic, but it is a high-affinity agonist that easily desensitizes NTRs. Results with non-glycosylated Contulakin-G suggested that such profound mechanistic differences between Contulakin-G and neurotensin can be accounted for by the presence of both, glycosylation and distinct N-terminal sequences. We propose to systematically explore structural differences between Contulakin-G and neurotensin that determine a unique pharmacological profile of this conopeptide. Specific aims of this proposal include: (1) chemical synthesis of Contulakin-G and neurotensin analogs varying in the peptidic and glycosyl structures, (2) characterization of in vitro pharmacological properties of Contulakin-G analogs, (3) assessment of analgesic properties of the synthesized ananlogs and their mechanism of analgesia, (4) discovery of novel members of the same gene family that Contulakin-G belongs to. Results from the research will allow to better define structural determinants of unique analgesic properties of Contulakin-G, as well as to test a hypothesis that the potent analgesia produced by this glycopeptide can, at least in part, be accounted for by its ability to not desensitize neurotensin receptor. The long-term outcomes of this proposal may lead to development of novel compounds targeting GPCRs.

该项目的长期目标是表征靶向G蛋白偶联受体（GPCR）的综合肽的结构，生化和药理特性。在拟议的研究中，我们将专注于研究独特的镇痛综合肽（contulakin-g）的结构活性关系，靶向 神经素受体（NTRS）。 Contulakin-G是一种从Conus Geographus毒液中分离出来的16个残留肽。该肽与内源性神经肽神经辛（NT）具有C末端序列相似性，但它还包含不寻常的翻译后修饰：THR残基的O-糖基化。 Contulakin-G的独特药理学特性是，这种非常有效的镇痛化合物是神经素受体的低亲和力，非脱离激动剂。与Contulakin-G形成鲜明对比的是，NT的效力降低了600倍，但它是一种高亲和力激动剂，很容易使NTR脱敏。结果 非糖基化的contulakin-g表明，可以通过存在，糖基化和不同的N末端序列来解释Contulakin-G和Neurotensin之间的如此深刻的机械差异。我们建议系统地探索Contulakin-G和 确定该综合肽独特的药理特征的神经素。该提案的具体目的包括：（1）肽和糖基结构中的二藻蛋白酶-G和神经素类似物的化学合成，（2）（2）表征contulakin-g模拟的体外药理特性，（3）（3） 评估合成的Ananlogs的镇痛性能及其镇痛机制，（4）发现Contulakin-G所属于的同一基因家族的新成员。研究的结果将允许更好地定义contulakin-G的独特镇痛性特性的结构决定因素，并检验一个假设，即该糖肽产生的有效镇痛可以在 至少在某种程度上是通过其不脱敏神经辛受体的能力来解释的。该提案的长期结果可能导致针对GPCR的新型化合物的发展。