Medicinal Chemistry and Chemical Proteomics of Ipomoeassin Natural Glycoresins

Ipomoeassin 天然糖树脂的药物化学和化学蛋白质组学

• 批准号: 8957589
• 负责人: Wei Shi
• 金额: $ 32.92万
• 依托单位: UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-05 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8957589
• 关键词: Affect; Affinity Chromatography; Antineoplastic Agents; Apoptosis; Binding Proteins; Biological; Biological Factors; Biology; Biomedical Research; Breast Cancer Cell; Cancer cell line; Carbohydrates; Cell Cycle Progression; Cell Line; Cell Proliferation; Cells; Cellular biology; Chemicals; Clinical; Complex; Development; Disease; Engineering; Evaluation; Family; Family member; Fatty Acids; Figs - dietary; Future; Gel; Glycosides; Goals; Growth; Health; Homo; Human; Human Genome; Image; Intervention; Ipomoea; Knowledge; Lead; Life; MDA MB 231; Macrocyclic Compounds; Macrolides; Malignant Neoplasms; Marketing; Mass Spectrum Analysis; Medical; Modification; Molecular Biology; Molecular Biology Techniques; Molecular Structure; Molecular Target; Morbidity - disease rate; Normal Cell; Outcome; Pattern; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Plant Resins; Plants; Positioning Attribute; Production; Protein Binding; Proteins; Proteomics; Research; Route; Set protein; Source; Structure-Activity Relationship; Suriname; Synthesis Chemistry; Tail; Techniques; Testing; Time; Use of New Techniques; base; biological systems; cancer cell; cell type; crosslink; cytotoxicity; design; drug candidate; drug development; drug discovery; human disease; improved; inhibitor/antagonist; insight; interdisciplinary approach; man; mortality; neoplastic; next generation; novel; prevent; success; therapeutic target; tool; ultraviolet irradiation

 DESCRIPTION (provided by applicant): To date, only a very small fraction of proteins encoded by the human genome have been targeted by clinical drugs. To reduce morbidity and mortality of existing and newfound diseases, there is a fundamental need to develop new pharmaceutical agents and identify novel biological targets for therapeutic and preventative interventions. Bioactive natural products are a rich source of drug candidates and are also important tools for exploring biological systems. The ipomoeassins are a family of carbohydrate-derived macrocyclic compounds isolated from the Suriname plant Ipomoea squamosal of the morning glory family. Some members of this family are very potent inhibitors (with IC50s in the low nanomolar range) of human cancer cells. In the NCI 60-cell line screen, ipomoeassin A, the naturally most abundant member of the family, showed strong and selective growth inhibition of different cancer cells, and its pattern of activity was clearly distinguished from other known anticancer agents based on a COMPARE analysis. Therefore, it suggests that the ipomoeassins have novel molecular targets and can serve as promising new leads for drug development. The long term goal of this project is to elucidate the mechanisms by which the ipomoeassins exert their biological activities and investigate the pharmaceutical potential of this family of natural macrocycles. The objectives of this proposal are 1) to elucidate structure-activity relationships (SAR) of ipomoeassin F, and 2) to synthesize bioactive photo-crosslinking activity-based probes (hvABPs) of ipomoeassin F to identify its molecular targets. Ipomoeassin F is selected for the proposed studies because it is the most potent member of the family. Our rationale for the proposed research is that SAR evaluation and target identification are critical not only for understanding the modes of action of the ipomoeassins but also to provide essential information that will facilitate their future medical evaluation and the design of new pharmaceutical agents derived from them. Our hypothesis is that the ipomoeassins achieve their biological activities by forming complexes with a unique set of proteins in cells. A novel quantitative chemical proteomics approach is employed to test this hypothesis. In brief, the information obtained from the SAR studies will be used to design and synthesize desired chemical probes. Subsequently, specific target proteins will be captured by the probes upon UV irradiation and visualized by in-gel fluorescent imaging. The detected protein candidates will then be isolated using affinity purification and characterized by mass spectrometry. Finally, the identified protein targets will be validated using cell and molecular biology techniques. The proposed research is significant because the acquired knowledge will open the door to designing the next generation of ipomoeassin derivatives to selectively perturb functions of those target proteins for preventing and/or treating human diseases including cancer.

 描述(申请人提供)：到目前为止，只有一小部分由人类基因组编码的蛋白质是临床药物的靶标。为了减少现有和新发现的疾病的发病率和死亡率，根本上需要开发新的药物制剂，并为治疗性和预防性干预确定新的生物靶点。生物活性天然产物是候选药物的丰富来源，也是探索生物系统的重要工具。Ipomoeassins是从牵牛花家族的苏里南植物Ipomoea squamosal中分离出来的碳水化合物大环化合物家族。这个家族的一些成员是非常有效的人类癌细胞抑制物(IC50在低纳摩尔范围内)。在NCI-60细胞系筛选中，Ipoomoeassin A是该家族中天然含量最丰富的成员，对不同的癌细胞具有很强的选择性生长抑制作用，通过比较分析，它的活性模式与其他已知的抗癌药物明显不同。因此，这表明ipomoeassins具有新的分子靶点，有望成为药物开发的新线索。这一项目的长期目标是阐明ipomoeassins发挥其生物活性的机制，并研究其药用潜力。 天然大循环家族。本建议的目的是1)阐明ipomoeassin F的构效关系(SAR)，2)合成ipomoeassin F的生物活性光交联活性探针(HvABPs)，以确定其分子靶标。Ipomoeassin F被选入拟议的研究，因为它是该家族中最有效的成员。我们建议进行这项研究的理由是，SAR评估和靶标识别不仅对于了解异丙酮类药物的作用模式至关重要，而且对于提供必要的信息，有助于它们未来的医学评估和由此衍生的新药物的设计至关重要。我们的假设是，ipomoeassins通过与细胞中一组独特的蛋白质形成复合体来实现其生物活性。一种新的定量化学蛋白质组学方法被用来检验这一假说。简而言之，从搜救研究中获得的信息将用于设计和合成所需的化学探针。随后，特定的目标蛋白将被紫外光照射的探针捕获，并通过凝胶内荧光成像进行可视化。然后，将使用亲和纯化方法分离检测到的候选蛋白质，并用质谱学进行表征。最后，将使用细胞和分子生物学技术对识别的蛋白质靶标进行验证。这项拟议的研究意义重大，因为所获得的知识将为设计下一代ipomoeassin衍生物打开大门，选择性地干扰这些靶蛋白的功能，以预防和/或治疗包括癌症在内的人类疾病。