Structures of Amphotericin-Sterol Complexes

两性霉素-甾醇复合物的结构

• 批准号: 9276846
• 负责人: Chad M Rienstra
• 金额: $ 9.94万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276846
• 关键词: Achievement; Affinity; Amphotericin; Amphotericin B; Anabolism; Antifungal Agents; Binding; Biological; Cells; Cholesterol; Clinical; Complex; Development; Ergosterol; Foundations; Freedom; Gold; Health; Human; In Vitro; Ion Channel; Label; Lead; Life; Ligands; Lipid Bilayers; Macrolides; Membrane; Methods; Modeling; Molecular Conformation; Mus; Mycoses; Natural Products; Organic Synthesis; Pharmaceutical Preparations; Polyenes; Porifera; Positioning Attribute; Refractory; Reporting; Resistance; Resolution; Sterols; Structure; Testing; Therapeutic Index; Urea; Vertebral column; antimicrobial; antimicrobial drug; base; cell killing; frontier; fungus; improved; in vitro activity; microbial; mortality; mycosamine; novel; polyol; small molecule; solid state nuclear magnetic resonance

DESCRIPTION (provided by applicant): This project aims to advance understanding of the mode of action of the clinically vital but also highly toxic antifungal drug amphotericin B (AmB). Alternative to the classic ion channel model, preliminary studies in this proposal show that AmB forms large extramembranous aggregates that extract sterols from lipid bilayers and thereby kill cells. This novel "sterol sponge" model illuminates a new and more actionable roadmap to an improved therapeutic index, i.e., maximize the relative binding affinity of the AmB sterol sponge for the sterol found in fungi (ergosterol) vs. humans (cholesterol). Aim 1 is to determine the structure of the AmB sterol sponge, assembled in the presence of physiologically relevant lipid bilayers. Aim 2 is to determine the structures of the complexes of the AmB sponge with ergosterol and cholesterol. Aim 3 is to determine the structure of the sterol sponge and corresponding ergosterol complex derived from a new derivative of AmB, AmBMU, which was recently discovered and shown to bind ergosterol but not cholesterol, to be non-toxic to human cells, and to retain potent antifungal activity in vitro and in mice. Collectively, these studies wll provide a high-resolution picture of the atomistic interactions that underlie the biological activities of AmB and thus powerfully enable the rational development of less toxic derivatives of this clinically vital natural product. These studies will also further illuminate the fundamental features of how clinically validated resistance-refractory antimicrobial action can be achieved and lay the foundation for the frontier pursuit of other biologically relevant small molecule-small molecule interactions. Relevance to Human Health. Amphotericin B is the powerful but unfortunately highly toxic gold standard therapy for treatment of systemic fungal infections, and this drug has uniquely evaded the emergence of microbial resistance despite more than half a century of widespread clinical utilization. Better understanding how AmB exerts its biological activities is thus critical for guiding the rational development of derivatives with an improved therapeutic index as well as other resistance-refractory antimicrobial agents.

描述（由申请人提供）：该项目旨在加深对临床上至关重要但毒性很强的抗真菌药物两性霉素 B (AmB) 作用方式的了解。作为经典离子通道模型的替代方案，该提案中的初步研究表明，AmB 形成大型膜外聚集体，从脂质双层中提取甾醇，从而杀死细胞。这种新颖的“甾醇海绵”模型阐明了一个新的、更可行的路线图，以提高治疗指数，即最大化 AmB 甾醇海绵对真菌（麦角甾醇）与人类（胆固醇）中发现的甾醇的相对结合亲和力。目标 1 是确定在生理相关脂质双层存在下组装的 AmB 甾醇海绵的结构。目标 2 是确定 AmB 海绵与麦角甾醇和胆固醇的复合物的结构。目标 3 是确定甾醇海绵和相应的麦角甾醇复合物的结构，该复合物源自 AmB 的新衍生物 AmBMU，最近发现并显示该衍生物可结合麦角甾醇但不结合胆固醇，对人体细胞无毒，并在体外和小鼠体内保留有效的抗真菌活性。总的来说，这些研究将提供 AmB 生物活性基础的原子相互作用的高分辨率图像，从而有力地促进这种临床上重要的天然产物的毒性较低的衍生物的合理开发。这些研究还将进一步阐明如何实现临床验证的耐药性抗菌作用的基本特征，并为其他生物学相关小分子的前沿探索奠定基础。 分子相互作用。 与人类健康的相关性。两性霉素 B 是治疗全身真菌感染的强效但不幸的是剧毒的金标准疗法，尽管半个多世纪以来临床广泛使用，但这种药物独特地避免了微生物耐药性的出现。因此，更好地了解 AmB 如何发挥其生物活性对于指导合理开发具有改善治疗指数的衍生物以及其他耐药性抗菌药物至关重要。