Synthesis and Study of Amphotericin B Derivatives

两性霉素B衍生物的合成与研究

基本信息

批准号：
8995207
负责人：
Martin D Burke
金额：
$ 44.58万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8995207
关键词：
Acids Acquired Immunodeficiency Syndrome Adverse effects Amphotericin Amphotericin B Antibiotic Resistance Antifungal Agents Binding Binding Sites Biological Biological Assay Calorimetry Carbon Dioxide Cells Cholesterol Complex Coupling Development Distant Dose-Limiting Elderly Electronics Ergosterol Fungal Drug Resistance Goals Gold Health Human Immune system Infection Ion Channel Lead Life Medicine Membrane Methods Modeling Modification Monte Carlo Method Mycoses Natural Products Organic Synthesis Patients Pharmaceutical Preparations Polyenes Reagent Role Series Site Sterols Structure-Activity Relationship Testing Therapeutic Index Time Titrations Toxic effect Yeasts antimicrobial appendage base chemotherapy clinically significant design effective therapy flexibility glycosylation improved killings microbial mycosamine research study self assembly small molecule standard care

项目摘要

DESCRIPTION (provided by applicant): Amphotericin has served as the gold standard for treatment of life-threatening systemic fungal infections for more than half a century, and resistance to this antibiotic remains exceptionally rare. However, amphotericin is also highly toxic, and thus the effective treatment of systemic fungal infections is all too often precluded, nt by a lack of efficacy, but by dose-limiting side effects. Because systemic fungal infections represent a major and growing threat to human health worldwide, a less toxic but equally effective amphotericin derivative stands to have a major impact. Recently, in contrast to the widely accepted channel model, we discovered that amphotericin primarily exerts its activity against yeast and human cells by simply binding ergosterol and cholesterol, respectively. Thus, rather than trying to promote the self-assembly of multimeric ion channels selectively in yeast vs. human cells, efforts toward an improved therapeutic index can now focus directly on the much simpler goal of more selectively binding ergosterol vs. cholesterol. To maximally enable the rational pursuit of this objective, we herein propose to harness the power of organic synthesis to systematically characterize the key structure-function relationships that underlie thi very rare type of small molecule-small molecule interaction. Collectively, these studies will substantially illuminate the fundamental underpinnings of AmB/sterol interactions that are central to the mechanism of action of this clinically vital antifungal agent, generate promising candidates for further development as antifungal agents with an improved therapeutic index, drive the continued development of a highly efficient and flexible building block-based platform for small molecule synthesis, as well as advance site-selective functionalizations as a powerful strategy for accessing targeted derivatives of complex natural products.

描述（由申请人提供）：两性霉素已成为危及生命的全身真菌感染的黄金标准，超过半个世纪，对这种抗生素的耐药性仍然极为罕见。但是，两性霉素也具有剧毒，因此，由于缺乏疗效，但由于剂量限制的副作用而有效地治疗了全身真菌感染的有效治疗。由于系统性真菌感染代表了全世界对人类健康的主要且日益严重的威胁，因此具有重大影响的毒性较小但同样有效的两性霉素衍生物立场。最近，与广泛接受的通道模型相反，我们发现两性霉素主要通过简单地结合麦格固醇和胆固醇来对酵母和人类细胞发挥其活性。因此，与其试图在酵母和人类细胞中选择性地促进多聚体离子通道的自组装，而是为改进的治疗指数的努力直接集中在更简单的目标上，即更简单的目标是更有选择性地结合麦角固醇与胆固醇。为了最大程度地实现这一目标的合理追求，我们在这里提出的是利用有机合成的力量，以系统地表征关键结构功能关系，这些关系是基于这种非常罕见的小分子 - 小分子相互作用的类型。总的来说，这些研究将基本上阐明AMB/固醇相互作用的基本基础，这是该临床上重要的抗真菌剂的作用机制至关重要访问复杂天然产物的靶向衍生物。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

From synthesis to function via iterative assembly of N-methyliminodiacetic acid boronate building blocks.

DOI：
10.1021/acs.accounts.5b00128
发表时间：
2015-08-18
期刊：
Accounts of chemical research
影响因子：
18.3
作者：
Li J;Grillo AS;Burke MD
通讯作者：
Burke MD

Synthesis of many different types of organic small molecules using one automated process.

DOI：
10.1126/science.aaa5414
发表时间：
2015-03-13
期刊：
Science (New York, N.Y.)
影响因子：
0
作者：
Li J;Ballmer SG;Gillis EP;Fujii S;Schmidt MJ;Palazzolo AM;Lehmann JW;Morehouse GF;Burke MD
通讯作者：
Burke MD

Nontoxic antimicrobials that evade drug resistance.

DOI：
10.1038/nchembio.1821
发表时间：
2015-07
期刊：
NATURE CHEMICAL BIOLOGY
影响因子：
14.8
作者：
Davis, Stephen A.;Vincent, Benjamin M.;Endo, Matthew M.;Whitesell, Luke;Marchillo, Karen;Andes, David R.;Lindquist, Susan;Burke, Martin D.
通讯作者：
Burke, Martin D.

Restored Physiology in Protein-Deficient Yeast by a Small Molecule Channel.