Synthesis and Study of Amphotericin B Derivatives

描述（由申请人提供）：本研究项目的总体目标是开发新的合成策略和方法，并利用它们在原子细节上表征两性霉素B （AmB）基于通道的作用机制，从而使这种具有临床重要性但也具有高毒性的抗真菌药物的治疗指标得到合理优化。计算机模拟研究预测，附加在天然产物上的某些protic官能团对AmB/胆固醇通道的自组装（导致毒性）至关重要，但对AmB/麦角甾醇通道（导致抗真菌活性）并不重要，因此导致以下假设：AmB治疗指数的改善可以通过选择性删除一个或多个这些protic官能团来实现。本研究项目旨在系统地验证这一假设。将开发新的合成策略和方法，使附加在两性霉素B上的12个质子官能团一次一个地被“删除”。类似于蛋白质科学中丙氨酸扫描的过程，每个质子功能基团缺失的后果将在一系列生物物理和生物分析中确定。非专业语言声明：被称为“两性霉素”的抗生素是目前治疗危及生命的真菌感染最有效的药物。然而，不幸的是，这种药物有许多毒副作用，经常限制其疗效。该研究项目旨在更清楚地了解两性霉素是如何起作用的，并通过有机合成和生物测定相结合，最大限度地减少这些毒副作用。

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.