Natural Product-Inspired Novel Synthetic Antiplasmodial Scaffolds

天然产物启发的新型合成抗疟原虫支架

• 批准号: 8872417
• 负责人: DEBOPAM CHAKRABARTI
• 金额: $ 7.22万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8872417
• 关键词: Address; Alkaloids; Antimalarials; Appearance; Applications Grants; Area; Artemisinins; Beryllium; Biological; Biological Assay; Biological Factors; Carbon; Cell Line; Cells; Cessation of life; Chemicals; Childhood; Clinical; Cluster Analysis; Collection; Combined Modality Therapy; Country; Cues; Data; Development; Disease; Dose; Drug resistance; Economics; Elements; Fluorescence; Goals; Growth; Laboratories; Libraries; Life; Malaria; Mammalian Cell; Memorial Sloan-Kettering Cancer Center; Metabolic; Nature; Parasite resistance; Parasites; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Prevalence; Property; Proteins; Research; Research Project Grants; Resistance; Role; SYBR Green I; Solubility; Source; Staging; Synthesis Chemistry; Testing; Therapeutic; Ursidae Family; artemisinine; base; cellular targeting; cheminformatics; chemotherapy; cytotoxicity; disorder control; drug discovery; innovation; interest; macromolecule; mortality; next generation; novel; pharmacophore; professor; programs; public health relevance; response; scaffold; screening; therapeutic development

 DESCRIPTION (provided by applicant): About three billion people live in malaria endemic areas and approximately 300 million will develop clinical cases of the disease. Emergence of malaria parasites resistant to all available drugs, unfortunately, makes the prospects of controlling the disease by chemotherapy very difficult. Most of the current antimalarials were developed decades ago and many are derived from older drugs. Because of this dire situation for malaria therapy it is extremely important to identify new potent and selective antiplasmodial chemotypes that are structurally distinct from existing antimalarials. It is believed that scaffold of natural product (NP) origin have structural cues that enable them to interact with proteins. Thus NPs exemplify privileged structural elements that can be exploited as pre-validated starting points for novel synthetic library creation. The proposed research project seeks to identify novel antiplasmodial compounds through unbiased cell-based screen of "natural product-inspired" compound libraries containing structurally diverse three-dimensional scaffolds containing an increased number of sp3-hybridized carbons. These compounds belong to underexplored areas of the chemical space. We hypothesize that NP-inspired synthetic scaffolds have a very high likelihood of yielding novel antimalarial chemotypes because of their high diversity that has not been previously explored for antimalarial development. To accomplish the objective of identifying new antiplasmodial compounds and prove our hypothesis, we plan to: (a) Screen natural product-inspired a BioDesign synthetic library, and a spiroketal, polyketide, alkaloid library to identify antiplasmodial scaffolds using an unbiased cel-based growth inhibition assay; (b) Determine selectivity, stage-specific activity, and pharmacological properties for prioritization of hits. The proposed research is highly innovative and significant as it addresses an unmet need in the field- new drug leads to support global malaria elimination campaign.

 描述（由适用提供）：约有30亿人居住在疟疾内部分子区域，大约3亿人将发展该疾病的临床病例。不幸的是，对所有可用药物的抗性疟原虫的出现使化学疗法控制这种疾病的前景非常困难。当前的大多数抗疟药是数十年前开发的，许多抗疟药来自较旧的药物。由于疟疾疗法的这种方向情况，确定与现有抗疟疾物质不同的新潜力和选择性抗流质化学型非常重要。据认为，天然产物的支架（NP）具有结构提示，使它们能够与蛋白质相互作用。 NP例证了特权的结构元素，这些元素可以作为新型合成库创建的预验证的起点进行探讨。拟议的研究项目旨在通过基于无偏细胞的“自然产物启发”化合物库来鉴定新型的抗血流化合物化合物，其中包含结构上多样的三维脚手架，其中含有增加数量的SP3-杂交碳。这些化合物属于化学空间的未置换区域。我们假设由NP启发的合成支架具有很高的产生新型抗疟疾化学型的可能性，因为它们的高多样性以前从未探索过抗疟发发育。为了实现确定新的抗血流化化合物并证明我们的假设的目的，我们计划：（a）屏幕自然产物启发的生物建筑合成图书馆，以及一个spiritoletal，polyketide，polykelide，balkaloid库，以使用基于基于基于CEL的CEL抑制抑制分析识别抗卵石型； （b）确定命中优先次序的选择性，特异性活性和药物特性。拟议的研究具有很高的创新性和重要意义，因为它解决了现场的未满足需求 - 新药导致支持全球消除疟疾运动。