Biosynthesis and Enzymology of Antifungal Natural Products

抗真菌天然产物的生物合成和酶学

基本信息

批准号：
10066257
负责人：
NEIL K GARG
金额：
$ 58.27万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-15 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10066257
关键词：
2-hydroxypyridine Acids Address Alder plant Alkaloids Amphotericin Anabolism Antifungal Agents Antifungal Therapy Azole resistance Biochemical Biochemical Reaction Biological Biological Models Catalysis Chemistry Comparative Study Complex Computing Methodologies Crystallization Cyclization Cyclohexanes Cytochrome P450 Drug resistance Electrons Engineering Enzymatic Biochemistry Enzymes Family Frequencies Genome Homologous Gene Infection Investigation Knowledge Methods Mining Natural Products Nature Outcome Paper Pathway interactions Pharmaceutical Preparations Play Property Reaction Research Role S-Adenosylmethionine Side Specificity Structure Therapeutic Tyrosine Work analog computational chemistry cycloaddition decalin drug discovery improved inhibitor/antagonist insight interest mortality multidisciplinary nanomolar pathogenic fungus prevent resistance mechanism respiratory scaffold weapons

项目摘要

ABSTRACT The combination of high frequencies of infection, high mortality rates, emergence of drug resistance, small number of therapeutic options and a depleted discovery pipeline has resulted in an urgent need for finding new antifungal molecules. Natural products, especially those produced by fungal species as natural antifungal weapons, have been and will continue to play important roles and provide leads for drug discovery. Realizing the immense potential of natural products as antifungal leads, and the prospects of discovering new structures through genome-guided methods, we are proposing a comprehensive and multidisciplinary project to investigate the biosynthesis of fungal-derived 2-pyridone alkaloids, which are complex natural products with potent and selective antifungal activities. We will be particularly focused on a diverse set of enzyme-catalyzed pericyclic reactions that give rise to the polycyclic scaffold important for biological activity. Uncovering these enzymes, followed by detailed investigation of the mechanisms and sequence-activity relationships, will improve our fundamental understanding of enzyme catalysis, and enable biosynthetic engineering approaches to generate natural product analogs, and expand genome mining leads for new antifungals. This multi-PI proposal bring together complementary expertise in three aspects of natural product research: biosynthesis, computational chemistry and synthesis. Together we will address three aims: 1) Investigate SAM-dependent pericyclase using leporin as a model system. 2) Investigate Alder-Ene and dephenylation reactions in pyridoxatin biosynthesis; and 3) Investigate biosynthesis of decalin-containing antifungal 2-pyridone compounds. Insights into the biosynthesis of these molecules will reveal fundamental insights into enzymes that catalyze pericyclic reactions, and provide leads for structure-guided natural product discovery.

抽象的感染频率高、死亡率高、耐药性出现，治疗选择数量较少和发现渠道耗尽导致迫切需要寻找新的抗真菌分子。天然产品，特别是由真菌物种产生的作为天然抗真菌剂的产品武器已经并将继续发挥重要作用，并为药物发现提供线索。实现天然产物作为抗真菌先导药物的巨大潜力以及发现新结构的前景通过基因组引导的方法，我们提出了一个全面的、多学科的项目来研究真菌衍生的 2-吡啶酮生物碱的生物合成，这是一种复杂的天然产物，具有有效和选择性抗真菌活性。我们将特别关注一系列不同的酶催化周环产生对生物活性重要的多环支架的反应。发现这些酶，随后详细研究机制和序列-活性关系，将提高我们的对酶催化的基本了解，并使生物合成工程方法能够产生天然产物类似物，并扩大新抗真菌药物的基因组挖掘线索。这个多PI提案带来了天然产物研究三个方面的互补专业知识：生物合成、计算化学和合成。我们将共同实现三个目标：1) 使用以下方法研究 SAM 依赖性周环化酶 leporin 作为模型系统。 2) 研究吡哆沙汀生物合成中的Alder-Ene和脱苯反应； 3) 研究含十氢萘的抗真菌 2-吡啶酮化合物的生物合成。洞察这些分子的生物合成将揭示催化周环反应的酶的基本见解，并为结构引导的天然产物发现提供线索。