Novel Antimalarials from Fungi

来自真菌的新型抗疟药

基本信息

批准号：
10166769
负责人：
DEBOPAM CHAKRABARTI
金额：
$ 75.82万
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/10166769
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 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

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.

疟疾仍然困扰着世界约一半人口，造成超过 40 万人死亡，其中大部分是孩子们。疟疾造成的全球经济损失是巨大的。目前大部分药物用于疟疾治疗的药物，包括基于青蒿素的联合治疗正在失去它们的有效性归因于耐药性的广泛出现。为了解决脆弱性疟疾治疗，我们建议通过筛选发现新型抗疟化合物真菌次生代谢物库。我们假设真菌的次生代谢产物抗疟药发现尚未得到充分探索，将为我们提供独特的机会研究医学相关但尚未开发的化学空间以发现新型疟疾疗法。该提案的前提是基于我们有希望的初步筛选，该筛选已鉴定出具有有效抗疟原虫活性的真菌提取物和真菌来源的纯化合物。为了证明这一假设，我们在此建议 (1) 筛选 10,000 个提取物的文库从不同的真菌物种中提取优先生物活性提取物，以识别和确定对多种病毒具有活性的选择性抗疟原虫化合物的结构寄生虫发育阶段；将筛选命中以确定交叉耐药性，并杀死速度。 (2) 活性化合物将通过体外理化、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下式确定：耐药性的体外进化，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。这项工作的研究将是通过 Debopam 实验室之间的多学科合作进行 Chakrabarti（中佛罗里达大学）、Robert Cichewicz（俄克拉荷马大学）、Kirsten Hanson（德克萨斯大学圣安东尼奥分校）、Elizabeth Winzeler 和 Jeremiah Momper （加州大学圣地亚哥分校）拥有天然产物化学方面的综合专业知识，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经过验证的目标的新型先导化合物治疗耐多药疟疾。