Synthesis and Study of Amphotericin B Derivatives

两性霉素B衍生物的合成与研究

• 批准号: 8078988
• 负责人: Martin D Burke
• 金额: $ 28.55万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078988
• 关键词: Adverse effects; Alanine; Alcohols; Amphotericin; Amphotericin B; Antibiotics; Antifungal Agents; Attenuated; Biological Assay; Biological Factors; Boronic Acids; Calorimetry; Cells; Cholesterol; Clinical; Collection; Complex; Computer Simulation; Coupling; Cytolysis; Data; Development; Dose-Limiting; Ergosterol; Erythrocytes; Goals; Growth; Human; Hybrids; Hydrogen; Industrial fungicide; Ion Channel; Ions; Language; Life; Ligands; Liposomes; Medicine; Membrane; Membrane Lipids; Methods; Modeling; Molecular Conformation; Mycoses; Organic Synthesis; Peptide Synthesis; Pharmaceutical Preparations; Play; Process; Proteins; Research; Research Personnel; Resistance; Role; Scanning; Science; Series; Structure; Structure-Activity Relationship; Techniques; Testing; Therapeutic Index; Time; Titrations; Toxic effect; Work; Yeasts; base; carbene; clinical efficacy; design; flexibility; functional group; improved; microbial; programs; research study; self assembly; small molecule

DESCRIPTION (provided by applicant): This overall goal of this research program is to develop new synthesis strategies and methods and use them to characterize the channel-based mechanism of action of amphotericin B (AmB) in atomistic detail, thereby enabling the rational optimization of the therapeutic index of this clinically-vital but also highly toxic antimycotic agent. Computer modeling studies predict that certain protic functional groups appended to the natural product are critical for self-assembly of the AmB/cholesterol channel (which leads to toxicity) but are not critical for the AmB/ergosterol channel (which leads to antifungal activity), thus leading to the following hypothesis: improvements in the therapeutic index of AmB can be achieved via the selective deletion of one or more of these protic functional groups. This research program aims to test this hypothesis systematically. New synthetic strategies and methods will be developed to enable the twelve protic functional groups appended to amphotericin B to be "deleted", one at a time. Analogous to the process of alanine scanning in protein science, the consequences of each protic functional group deletion will be determined in a battery of biophysical and biological assays. Statement in lay language: The antibiotic called "amphotericin" is the most effective medicine currently available for the treatment of life- threatening fungal infections. Unfortunately, however, this drug has many toxic side-effects that often limit its efficacy. This research program aims to understand more clearly how amphotericin works and minimize these toxic side-effects using a combination of organic synthesis and biological assays.

描述（由申请人提供）：该研究计划的总体目标是制定新的合成策略和方法，并使用它们来以原子性细节来表征两性霉素B（AMB）的基于渠道的作用机理，从而实现了该临床上有效但也具有强大有毒的抗肿瘤剂的治疗指数的合理优化。计算机建模研究预测，附加到天然产物上的某些原始功能组对于AMB/胆固醇通道的自组装至关重要（这导致毒性），但对于AMB/Ergosterol通道（导致抗真菌活性导致抗真菌活性）并不重要，因此会导致以下假设：通过AMB的治疗索引进行改进，可以通过一种选择性的功能来实现。该研究计划旨在系统地检验这一假设。将开发新的合成策略和方法，以使附加到两性霉素B的十二个原始官能团一次被“删除”。类似于蛋白质科学中丙氨酸扫描的过程，每个原始功能组缺失的后果将在一系列生物物理和生物学测定中确定。外行语言的陈述：称为“两性霉素”的抗生素是目前可用于治疗生命威胁真菌感染的最有效药物。但是，不幸的是，这种药物具有许多有毒的副作用，通常会限制其功效。该研究计划旨在更清楚地了解两性霉素的工作原理，并使用有机合成和生物学测定的结合来最大程度地减少这些有毒的副作用。