Structures of Amphotericin-Sterol Complexes

两性霉素-甾醇复合物的结构

• 批准号: 9179658
• 负责人: Chad M Rienstra
• 金额: $ 43.72万
• 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/9179658
• 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; Physiological; 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; public health relevance; 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）：该项目旨在提高人们对临床上至关重要但也有毒的抗真菌药物两性霉素B（AMB）的作用方式的理解。替代经典离子通道模型，该提案中的初步研究表明，AMB形成了大型的外膜外聚集体，从脂质双层提取固醇，从而杀死细胞。这个小说的“固醇海绵”模型阐明了一个新的，更可行的路线图，以改善治疗指数，即，最大化AMB固醇海绵对真菌（麦角固醇）与人（胆固醇）中固醇的相对结合亲和力。目的1是确定在存在与生理相关的脂质双层的情况下组装的AMB固醇海绵的结构。目标2是确定AMB海绵与麦角固醇和胆固醇的结构。 AIM 3是为了确定固醇海绵的结构和相应的麦角固醇复合物的结构，该结构源自AMB的新衍生物AMBMU，该衍生物最近被发现并证明是结合麦角固醇而非胆固醇，以对人类细胞无毒，并保留在体内和小鼠中的耐药性抗真菌活性。总的来说，这些研究提供了基于AMB的生物学活性的原子相互作用的高分辨率图，从而有效地使该临床上重要的天然产物的毒性较小的衍生物的合理发展。这些研究还将进一步阐明如何实现临床验证的抗性抗菌抗菌作用的基本特征，并为前沿追求其他生物学相关的小分子小分子奠定了基础 分子相互作用。 与人类健康有关。两性霉素B是一种强大但不幸的剧毒金标准疗法，用于治疗全身真菌感染，尽管超过半个世纪的广泛临床利用，这种药物已独特地避免了微生物耐药性的出现。因此，更好地了解AMB如何发挥其生物学活性对于指导具有改善的治疗指数以及其他耐药性抗药性抗菌药物的衍生物的合理发展至关重要。