Target-specific antimalarial compound identification using phenotypic assays

使用表型分析鉴定靶标特异性抗疟化合物

• 批准号: 10177856
• 负责人: JACQUIN C NILES
• 金额: $ 37.65万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-03 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177856
• 关键词: Address; Alanine-tRNA Ligase; Amino Acyl-tRNA Synthetases; Antimalarials; Biochemical; Biological; Biological Assay; Biological Process; Biology; Biophysics; Categories; Cell membrane; Cells; Chemicals; Clinical; Collection; Consumption; Development; Drug Targeting; Enzymes; Evaluation; Foundations; Future; Genetic; Goals; Human; Hypersensitivity; In Situ; Integral Membrane Protein; Knowledge; Lead; Libraries; Literature; Malaria; Mediating; Membrane; Metabolism; Mission; Molecular Target; Multi-Drug Resistance; Outcome; Parasite resistance; Parasites; Pathway interactions; Pharmaceutical Preparations; Phenotype; Plasmodium; Plasmodium falciparum; Play; Process; Property; Protein Biosynthesis; Proteins; Public Health; Publishing; Recombinant Proteins; Recombinants; Research; Resistance; Specific qualifier value; Standardization; Structure; Therapeutic; Time; Traumeel S; United States National Institutes of Health; base; biophysical properties; burden of illness; drug candidate; drug development; drug discovery; genomic data; human pathogen; improved; in vitro activity; innovation; knock-down; new therapeutic target; novel; pre-clinical; resistance mechanism; response; scaffold; screening; small molecule; therapeutically effective; tool; unpublished works; Address; Alanine-tRNA Ligase; Amino Acyl-tRNA Synthetases; Antimalarials; Biochemical; Biological; Biological Assay; Biological Process; Biology; Biophysics; Categories; Cell membrane; Cells; Chemicals; Clinical; Collection; Consumption; Development; Drug Targeting; Enzymes; Evaluation; Foundations; Future; Genetic; Goals; Human; Hypersensitivity; In Situ; Integral Membrane Protein; Knowledge; Lead; Libraries; Literature; Malaria; Mediating; Membrane; Metabolism; Mission; Molecular Target; Multi-Drug Resistance; Outcome; Parasite resistance; Parasites; Pathway interactions; Pharmaceutical Preparations; Phenotype; Plasmodium; Plasmodium falciparum; Play; Process; Property; Protein Biosynthesis; Proteins; Public Health; Publishing; Recombinant Proteins; Recombinants; Research; Resistance; Specific qualifier value; Standardization; Structure; Therapeutic; Time; Traumeel S; United States National Institutes of Health; base; biophysical properties; burden of illness; drug candidate; drug development; drug discovery; genomic data; human pathogen; improved; in vitro activity; innovation; knock-down; new therapeutic target; novel; pre-clinical; resistance mechanism; response; scaffold; screening; small molecule; therapeutically effective; tool; unpublished works

Our ability to effectively treat malaria is threatened by increasingly widespread resistance to the limited number of frontline antimalarial drugs available. Therefore, new strategies for identifying novel chemical probes and/or therapeutic leads centered around biologically validated targets are critically needed. Here, we propose the integrated use of functional genetics and chemical biology approaches to enable more effective target-driven antimalarial drug discovery. The long-term goal is to take advantage of recent advances in malaria parasite genetics to qualify and prioritize previously unexplored biological targets and/or pathways for therapeutics discovery efforts. By focusing on this target category, we envision achieving the capability to discover chemical probes that better allow us to define fundamental biology and elucidate new options for antimalarial therapy, and ultimately identify effective therapeutic strategies against multidrug resistant parasites that are becoming increasingly prevalent and widespread. While target-based drug discovery is conceptually appealing, it has not been as successful as phenotypic screens in identifying approved antimalarial agents. However, given the substantial amount of genomics data and the improved functional genetics tools now available, more effective approaches for target-based discovery could dramatically improve this. The objectives of this research are to (1) establish an innovative approach for improving target-specific drug discovery while (2) seeking to determine potential probe/drug-like molecules that are selective against several prioritized target candidates. While it relatively is straightforward to discover small molecules with in vitro activity against a target, prioritizing compounds that truly act via that target to dictate the biological outcome has been challenging. Conversely, phenotypic screens immediately establish the biological efficacy of a given compound. However, identifying the target(s) through which these compounds act biologically is time consuming and often unsuccessful. In both cases, the ability to synergistically leverage empirical and rational (e.g. structure-based) approaches for lead compound optimization is adversely impacted. In this proposal, we integrate use of state-of-the-art functional genetic tools to encode target-specific information into phenotypic screens to facilitate rapid identification of compounds interacting with pre-specified targets. We seek to establish a generalized framework applicable to a broad range of targets varying in their proposed biological function, subcellular localization, biochemical and biophysical properties. We envision developing standardized assays and analytical pipelines to facilitate evaluation of various compound collections. The current proposal will focus on developing and validating low- to-moderate throughput assays. The proposed research is significant because it simultaneously leverages key strengths of using target-specific and phenotypic screens in malaria parasites into a rapid, robust and potentially scalable process that can contribute overall to improving the efficiency with which therapeutically valuable targets and lead compounds are advanced during preclinical translational efforts.

我们有效治疗疟疾有效治疗的能力受到对有限数量的越来越广泛的抵抗力的威胁 可用的前线抗疟药。因此，确定新型化学探针和/或的新策略 急需以生物学验证的靶标为中心。在这里，我们建议 功能遗传学和化学生物学方法的综合使用，以实现更有效的目标驱动 抗疟药发现。长期目标是利用疟疾寄生虫的最新进展 遗传学符合先前未开发的生物学靶标和/或治疗途径的遗传学 发现工作。通过关注此目标类别，我们设想实现发现化学的能力 使我们更好地定义基本生物学并阐明抗疟疾疗法的新选择的探针， 并最终确定有效的治疗策略，以抵抗已成为的多药抗性寄生虫 越来越普遍且广泛。尽管基于目标的药物发现在概念上具有吸引力，但尚未 在识别认可的抗疟药剂时，与表型筛选一样成功。但是，给定 现在可用的大量基因组数据和改进的功能遗传学工具，更有效 基于目标的发现的方法可以极大地改善这一点。这项研究的目标是 （1）建立一种创新的方法来改善特定于靶标的药物发现，而（2）寻求确定 针对几个优先级候选者有选择性的潜在探针/药物样分子。同时 相对直接发现具有对靶标的体外活性的小分子，优先考虑 真正通过该靶标决定生物学结果的化合物是具有挑战性的。反过来， 表型筛选立即建立给定化合物的生物学功效。但是，确定 这些化合物在生物学上采用的目标是耗时，而且通常不成功。在这两个中 案例，能够协同利用经验和理性（例如基于结构）的方法的能力来铅 复合优化受到不利影响。在此提案中，我们整合了最先进功能的使用 遗传工具将特定于目标信息编码到表型屏幕中，以促进快速识别 化合物与预先指定的靶标相互作用。我们试图建立适用于 其提出的生物学功能，亚细胞定位，生化和 生物物理特性。我们设想开发标准化测定和分析管道以促进 评估各种复合收集。当前的建议将着重于开发和验证低 - 适度的吞吐量测定。拟议的研究很重要，因为它同时利用 在疟疾寄生虫中使用靶标特异性和表型筛选的关键优势 潜在的可扩展过程，可以总体上有助于提高治疗的效率 在临床前翻译工作期间，有价值的靶标和铅化合物是先进的。