Small molecule inhibitors of group II introns for treatment of fungal infections

用于治疗真菌感染的 II 族内含子小分子抑制剂

• 批准号: 8976883
• 负责人: Michael Christopher Van Zandt
• 金额: $ 22.4万
• 依托单位: NEW ENGLAND DISCOVERY PARTNERS, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8976883
• 关键词: Acquired Immunodeficiency Syndrome; Antifungal Agents; Bacteria; Biochemical; Candida albicans; Catalytic RNA; Cells; Chemicals; Chemistry; Complex; Crystallography; Development; Drug Design; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Eukaryota; General Population; Goals; Growth; Human; Human Cell Line; Immunocompromised Host; Individual; Infection; Inhibitory Concentration 50; Introns; Investigation; Knowledge; Lead; Mammalian Cell; Metabolic; Metabolism; Minimum Inhibitory Concentration measurement; Modeling; Modification; Molecular; Morbidity - disease rate; Mycoses; Neonatal; Organism; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Play; Public Health; RNA; RNA Processing; RNA Splicing; Ribosomes; Solid; Source; Staging; Staphylococcus aureus; Structure; Therapeutic; Toxic effect; Vertebrates; Work; Yeasts; antimicrobial; base; combat; design; drug discovery; foot; fungus; high throughput screening; in vitro Assay; inhibitor/antagonist; microbial; mortality; next generation; novel; novel strategies; pathogen; pharmacophore; programs; public health relevance; scaffold; screening; small molecule

 DESCRIPTION (provided by applicant): This project will result in the development of potent new inhibitors for a novel enzyme target that is specific to the metabolism of fungi and yeast: the group II self-splicing intron. This structurally complex and highly conserved ribozyme plays a key role in RNA processing and metabolic function of lower eukaryotes, but it is not present in humans and other vertebrates. Group II intron inhibitors therefore present a specific and potentially powerful new approach for combating pathogenic fungi and yeast, which represent a major public health problem for which therapeutic strategies are increasingly limited. Indeed, fungal infections are a major source of mortality and morbidity among AIDS patients, neonatal patients, and as these pathogens diversify, even among the noncompromised general population. Extensive biochemical studies have resulted in a complete enzymological framework for group II intron ribozymes, and group II intron structures in multiple stages of splicing have been thoroughly characterized through crystallography. With this groundwork in place, it is now possible to initiate a drug discovery program that is designed to identify potent small molecule inhibitors of this promising and novel target. Building on initial small molecule screening efforts (which yielded inhibitors with Ki values of 2-8 µM), we will synthesize the next generation of compounds, optimizing at least two types of initial leads through iterative modification of molecular scaffolds and structure-guided SAR. Small molecule design and synthesis will be done in rapid sequence with subsequent biochemical and cell-based analyses to evaluate potency and efficacy. Our goal in Phase 1 is to identify novel group II inhibitors with Ki values of < 200 nM, to evaluate their effects on growth of pathogenic fungi and bacteria (which also contain group II introns), and to evaluate compound toxicity in mammalian cells. Completion of these focused objectives will provide a solid footing for a subsequent Phase 2 program in group II intron antifungal therapeutics.

 描述(申请人提供)：该项目将针对真菌和酵母新陈代谢的一种新的酶靶标，开发有效的新抑制剂： 组II自剪接内含子。这种结构复杂且高度保守的核酶在低等真核生物的RNA加工和代谢功能中发挥着关键作用，但它在人类和其他脊椎动物中不存在。因此，第二组内含子抑制剂为对抗病原真菌和酵母菌提供了一种特异的、潜在有效的新方法，这是一个主要的公共卫生问题，其治疗策略越来越有限。事实上，真菌感染是艾滋病患者、新生儿患者死亡和发病的主要来源，而且随着这些病原体的多样化，即使在未受影响的普通人群中也是如此。广泛的生化研究已经形成了一个完整的第二组内含子核酶的酶学框架，并通过结晶学对剪接多个阶段的第二组内含子结构进行了彻底的表征。有了这些基础工作，现在就有可能启动一个药物发现计划，旨在识别这个有希望的新靶点的有效小分子抑制剂。在最初的小分子筛选工作(产生KI值为2-8微米的抑制剂)的基础上，我们将合成下一个 生成化合物，通过分子支架和结构导引的SAR的迭代修饰，优化至少两种类型的初始引线。小分子的设计和合成将按快速顺序进行，随后将进行生化和基于细胞的分析，以评估效力和疗效。我们在第一阶段的目标是识别新的II组抑制剂 ~lt；200 nM的KI值，以评价它们对病原真菌和细菌(也含有第二组内含子)生长的影响，并评价其对哺乳动物细胞的复合毒性。这些重点目标的完成将为第二组内含子抗真菌疗法的后续第二阶段计划提供坚实的基础。