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.

疟疾仍然困扰着大约一半的世界人口，造成40多万人死亡，其中大多数是 孩子疟疾造成的全球经济损失是巨大的。目前大多数药物 包括青蒿素类复方疗法在内的疟疾治疗药物的使用正在减少， 它们的有效性是由于抗药性的广泛出现。为了解决脆弱的 疟疾治疗，我们建议发现新的抗疟化合物，通过筛选一个 真菌次级代谢产物库。我们假设真菌的次级代谢产物， 在抗疟药物的发现上还没有得到充分的探索，这将为我们提供一个独特的机会， 研究与医学相关但尚未开发的化学空间，以发现新型疟疾 治疗学这一建议是基于我们有希望的初步筛选， 鉴定了真菌提取物和真菌来源的具有有效抗疟原虫活性的纯化合物。 为了证明这一假设，我们在此提出：（1）筛选10，000个提取物的文库， 从不同的真菌物种和去复制优先生物活性提取物，以确定和 确定选择性抗疟原虫化合物的结构， 寄生虫发育阶段;筛选命中以确定交叉抗性和杀灭 率(2)将通过体外理化、体内药理学对活性化合物进行优先排序 和体内功效研究。(3)优先打击的目标识别将由 体外抗性进化，随后进行全基因组测序。目标验证将是 通过CRISPR/Cas9介导的基因组编辑进行。这项奋进将是 通过Debopam实验室之间的多学科合作进行 Chakrabarti（中央佛罗里达大学），Robert Cichewicz（俄克拉荷马州大学），Kirsten Hanson（德克萨斯大学圣安东尼奥分校），Elizabeth Winzeler和Jeremiah Momper （加州圣地亚哥大学）与天然产物化学的综合专业知识， 疟疾细胞生物学、抗感染药物发现、靶标鉴定和验证。这是一个高度 重要的奋进，因为我们将发现新的先导化合物， 对多药耐药疟疾的治疗。