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Novel Antimalarials from Fungi

来自真菌的新型抗疟药

基本信息

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
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/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

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.

疟疾仍然折磨着世界上大约一半的人口，造成40多万人死亡