Synthesis and Study of Amphotericin B Derivatives

描述（由申请人提供）：本研究计划的总体目标是开发新的合成策略和方法，并使用它们以原子细节表征阿替霉素B（AmB）的基于通道的作用机制，从而能够合理优化这种临床上重要但也是高毒性的抗霉菌剂的治疗指数。计算机模拟研究预测，某些附加到天然产物上的质子官能团对于AmB/胆固醇通道的自组装至关重要（这导致毒性），但对AmB/麦角固醇通道不是关键的（这导致抗真菌活性），从而导致以下假设：AmB治疗指数的改善可以通过选择性缺失这些质子官能团中的一个或多个来实现。本研究计划旨在系统地验证这一假设。将开发新的合成策略和方法，以使附加到阿替霉素B上的12个质子官能团被“删除”，一次一个。类似于蛋白质科学中的丙氨酸扫描过程，每个质子官能团缺失的后果将在一系列生物物理和生物测定中确定。外行语言的陈述：这种名为“阿替霉素”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，往往限制其疗效。这项研究计划旨在更清楚地了解阿替西汀是如何工作的，并使用有机合成和生物测定的组合来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.