Natural Product-Inspired Novel Synthetic Antiplasmodial Scaffolds

 描述(申请人提供)：大约30亿人生活在疟疾流行地区，大约3亿人将出现这种疾病的临床病例。不幸的是，对所有可用药物产生抗药性的疟疾寄生虫的出现，使通过化疗控制疾病的前景变得非常困难。目前的大多数抗疟疾药物都是几十年前开发的，许多都是从较老的药物中提取出来的。由于疟疾治疗的这种严峻形势，确定在结构上与现有抗疟疾药物不同的新的有效和选择性的抗疟药化学类型是极其重要的。人们认为天然产物(NP)来源的支架具有结构线索，使其能够与蛋白质相互作用。因此，NP例证了特权结构元素，这些结构元素可以被用作创建新的合成文库的预先验证的起点。这项拟议的研究项目试图通过基于细胞的无偏筛选来鉴定新的抗疟原虫化合物，这些化合物库中含有结构多样化的三维支架，其中含有越来越多的SP3杂化碳。这些化合物属于化学领域中未被开发的领域。我们假设，NP激发的合成支架具有非常高的可能性产生新的抗疟疾化学类型，因为它们的高度多样性以前没有被探索用于抗疟疾的开发。为了完成鉴定新的抗疟原虫化合物并验证我们的假设的目标，我们计划：(A)筛选受天然产物启发的BioDesign合成库，以及螺酮、聚酮、生物碱库，以使用基于CEL的无偏生长抑制试验来鉴定抗疟原虫支架；(B)确定选择性、阶段特异性活性和药理学性质，以确定HITS的优先顺序。这项拟议的研究具有很高的创新性和重大意义，因为它解决了该领域一个未得到满足的需求--新药导致支持全球消除疟疾运动。

 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.