Novel Antimalarials from Fungi

来自真菌的新型抗疟药

基本信息

批准号：
10614534
负责人：
DEBOPAM CHAKRABARTI
金额：
$ 75.59万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
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/10614534
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 Classification Clinical Combined Modality Therapy 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 Medicine 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 Predisposition 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 Validation Vietnam cellular targeting comparative disorder control 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 pharmacologic pharmacophore resistant strain scaffold screening secondary metabolite small molecule therapeutics targeted treatment whole genome

项目摘要

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.

疟疾仍然折磨着大约一半的世界人口，造成超过400,000人死亡，主要是孩子们。疟疾的全球经济损失是巨大的。当前的大多数药物用于疟疾治疗的使用，包括基于青蒿素的组合疗法正在丢失它们由于耐药性的广泛出现而引起的有效性。解决的脆弱性疟疾疗法，我们建议通过筛查A发现新型抗疟疾化合物真菌二级代谢产物库。我们假设这种真菌次生代谢产物，对抗疟疾发现的疏忽不充分，将为我们提供一个独特的机会研究与发现新型疟疾的药物相关但未开发的化学空间疗法。该提案的前提是基于我们有希望的初步屏幕通过有效的抗血流活性确定了真菌起源的真菌提取物和纯化合物。为了证明这一假设，我们在本文中提出了（1）屏幕10,000个提取物的库从各种真菌物种和删除优先的生物活性提取物中，以识别和确定有效的选择性抗白杂种化合物的结构寄生虫发育阶段；命中将被筛选以确定交叉抗性和杀戮速度。（2）活性化合物将通过体外物理学，体内药理学优先考虑和体内功效研究。（3）优先命中的目标识别将由In确定抗性的体外演变，然后是整个基因组测序。目标验证将是由CRISPR/CAS9介导的基因组编辑进行。这项努力的研究将是通过Debopam实验室之间的多学科合作进行 Chakrabarti（佛罗里达州中部大学），罗伯特·塞切维奇（俄克拉荷马大学），柯斯滕汉森（德克萨斯大学圣安东尼奥大学），伊丽莎白·温泽勒和耶利米·莫珀（加利福尼亚大学圣地亚哥分校）具有自然产品化学专业知识，疟疾细胞生物学，抗感染发现，靶标识别和验证。这是一个高度重大努力，因为我们将发现具有验证靶标的新型铅化合物针对多药抗性疟疾的治疗。