Novel Antimalarials from Fungi

来自真菌的新型抗疟药

• 批准号: 10388240
• 负责人: DEBOPAM CHAKRABARTI
• 金额: $ 75.69万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-18 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388240
• 关键词: Address; Anti-Infective Agents; Antimalarials; Appearance; Area; Artemisinins; Bioinformatics; Biological; CRISPR/Cas technology; California; Cellular biology; Cessation of life; Chemicals; Child; Childhood; Clinical; Copy Number Polymorphism; Country; Data; Development; Disease; Drug Kinetics; Drug resistance; Economics; Effectiveness; Evolution; Florida; Growth; High Pressure Liquid Chromatography; In Vitro; Individual; Interdisciplinary Study; Laboratories; Lead; Libraries; Liver; Malaria; Measures; Mediating; Methods; Modeling; Molds; Molecular Target; Multi-Drug Resistance; Mus; Mutation; Myanmar; NMR Spectroscopy; Natural Products; Natural Products Chemistry; Natural Selections; Nature; Oklahoma; Parasite resistance; Parasites; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Prevalence; Property; Proteins; Proteome; Research; Resistance; Resistance profile; Resolution; Resource Development; Resources; Source; Southeastern Asia; Specimen; Spectrometry, Mass, Electrospray Ionization; Structure; Texas; Therapeutic; Time; Universities; Ursidae Family; Validation; Vietnam; base; cellular targeting; comparative; drug discovery; efficacy evaluation; efficacy study; experience; fungus; genome editing; genome sequencing; global health; improved; in vivo; in vivo evaluation; macromolecule; mortality; next generation; novel; novel lead compound; novel therapeutics; pharmacophore; resistant strain; scaffold; screening; small molecule therapeutics; targeted treatment; whole genome

Malaria still afflicts about half of the world population causing more than 400,000 deaths, mostly children. The global economic toll of malaria is enormous. Most of the drugs that are currently utilized for malaria treatment, including artemisinin-based combination treatments are losing their effectiveness due to widespread emergence of drug resistance. To address the fragility of malaria therapy, we propose to discover novel antimalarial compounds through screening of a library of fungal secondary metabolites. We hypothesize that fungal secondary metabolites, which are underexplored for antimalarial discovery, will provide us with a unique opportunity to investigate medicinally relevant but untapped chemical space for the discovery of novel malaria therapeutics. Premise for this proposal is based on our promising preliminary screen that has identified fungal extracts and pure compounds of fungal origin with potent antiplasmodial activities. To prove this hypothesis, we propose herein to (1) Screen a library of 10,000 extracts derived from diverse fungal species and dereplicate prioritized bioactive extracts to identify and determine structures of selective antiplasmodial compounds that are active against multiple parasite developmental stages; hits will be screened to determine cross-resistance, and killing rate. (2) Active compounds will be prioritized by in vitro physicochemical, in vivo pharmacology and in vivo efficacy studies. (3) Target identification of prioritized hits will be determined by in vitro evolution of resistance followed by whole genome sequencing. Target validation will be conducted by CRISPR/Cas9 mediated genome editing. The research in this endeavor will be conducted through a multidisciplinary collaboration between the laboratories of Debopam Chakrabarti (University of Central Florida), Robert Cichewicz (University of Oklahoma), Kirsten Hanson (University of Texas San Antonio), Elizabeth Winzeler and Jeremiah Momper (University of California San Diego) with combined expertise in natural product chemistry, malaria cell biology, anti-infective discovery, target identification, and validation. This is a highly significant endeavor, as we will discover novel lead compounds with validated targets for therapy against multidrug resistant malaria.

疟疾仍然困扰着世界上大约一半的人口，导致40多万人死亡，其中大部分 孩子们。疟疾在全球造成的经济损失是巨大的。目前使用的大多数药物 用于疟疾治疗，包括以青蒿素为基础的联合治疗正在失败 它们的有效性归功于广泛出现的耐药性。要解决脆弱的问题 在疟疾治疗方面，我们建议通过筛选一种新的抗疟疾化合物 真菌次生代谢物库。我们假设真菌次生代谢物， 对于抗疟疾发现的探索不足，将为我们提供一个独特的机会 调查与医学相关但尚未开发的化学空间，以发现新的疟疾 治疗学。此提案的前提是基于我们前景看好的初步筛选，该筛选具有 鉴定真菌提取物和真菌来源的纯化合物，具有强大的抗疟原虫活性。 为了证明这一假设，我们在这里建议(1)筛选一个由10,000个提取物组成的文库 从不同的真菌物种和取消复制优先生物活性提取物，以识别和 确定选择性抗疟原虫化合物的结构，这些化合物对多种 寄生虫的发育阶段；将对命中率进行筛选，以确定交叉耐药性和杀伤力 费率。(2)体外物理化学、体内药理学将优先考虑活性物质 和体内疗效研究。(3)优先命中的目标标识将由In确定 抗性的体外进化和全基因组测序。目标验证将是 由CRISPR/Cas9介导的基因组编辑进行。这项工作的研究将是 通过Debopam实验室之间的多学科合作进行 查克拉巴蒂(中佛罗里达大学)、罗伯特·奇切维茨(俄克拉荷马大学)、柯尔斯滕 汉森(德克萨斯大学圣安东尼奥分校)，伊丽莎白·温泽勒和耶利米·蒙珀 (加州大学圣地亚哥分校)拥有天然产品化学的综合专业知识， 疟疾细胞生物学、抗感染药物发现、目标识别和验证。这是一个高度的 重大的努力，因为我们将发现新的先导化合物，具有有效的目标 治疗耐多药疟疾。