Natural Product-Inspired Novel Synthetic Antiplasmodial Scaffolds

 描述（由申请人提供）：约有30亿人生活在疟疾流行地区，约有3亿人将出现该疾病的临床病例。不幸的是，疟疾寄生虫对所有可用药物都具有抗药性，这使得通过化学疗法控制这种疾病的前景变得非常困难。目前的大多数抗疟药是几十年前开发的，许多是从旧药物中提取的。由于疟疾治疗的这种可怕的情况，识别结构上不同于现有抗疟药的新的有效和选择性抗疟原虫化学型是极其重要的。据信，天然产物（NP）来源的支架具有使其能够与蛋白质相互作用的结构线索。因此，NPs具有特权的结构元件，可以用作新合成文库创建的预先验证的起点。拟议的研究项目旨在通过基于细胞的无偏筛选“天然产物启发”化合物库来确定新型抗疟原虫化合物，该化合物库包含结构多样的三维支架，其中含有更多的sp3杂交碳。这些化合物属于化学空间中未被探索的领域。我们假设，NP启发的合成支架有一个非常高的可能性产生新的抗疟化学型，因为他们的高度多样性，以前没有探索抗疟的发展。为了实现识别新的抗疟原虫化合物的目标并证明我们的假设，我们计划：（a）筛选天然产物启发的BioDesign合成文库，以及螺缩酮、聚酮化合物、生物碱文库，以使用无偏的基于细胞的生长抑制测定来识别抗疟原虫支架;（B）确定选择性、阶段特异性活性和药理学性质，以优先排序命中。拟议的研究具有高度创新性和重要性，因为它解决了该领域未满足的需求-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.