novel macrolides as anti-infective drugs

描述（由申请人提供）：尽管早已知道大环内酯糖基化对于抗菌活性是绝对必要的，但巨霉素（其与红霉素的区别仅在于在大环内酯的C6处连接了额外的糖）是第一种显示出显著的抗病毒和抗寄生虫活性的大环内酯。这些新的活动，独特的C6-糖基化的大环内酯类，建议从他们的能力，导致异常糖基化的蛋白质必不可少的病毒/寄生虫的发展。考虑到大环内酯糖基化在定义这种经验证的药物支架的最终抗菌、抗病毒和/或抗寄生虫潜力中的作用，一种简单、快速、稳健的“糖随机化”大环内酯的方法可能会发现广泛的抗感染药物先导物。虽然大环内酯半合成已经允许生产许多第二代和第三代大环内酯类似物，但令人惊讶地缺乏差异糖基化的类似物-主要是由于经典糖基化方法施加的严重限制。本申请中提出的研究旨在评估Centrose的专利技术（称为neoglycorandomization）在实现这一目标方面的效用。在本I期提案中，我们将通过合成和评价两种原型大环内酯新糖苷系列来证明创建用于鉴定抗感染先导化合物的差异糖基化酮内酯文库的可行性。"A型“C6原型设计基于具有显著抗菌、抗病毒和抗寄生虫活性的天然存在的C6 O-糖苷先例（巨霉素），而”B型“C9原型设计基于具有显著抗菌性质的第二代大环内酯（罗红霉素）内的非碳水化合物聚醚C9-修饰。这两种原型都是基于被称为大环内酯耐药性非诱导剂（例如MLSB）的酮内酯支架，预计这些修饰会增强结合相互作用并可能影响大环内酯刚性。将产生50个原型A和50个原型B类似物，并将其作为抗菌剂和抗病毒药进行特异性筛选。考虑到巨霉素的独特活性，预计对所提出的新糖基化原型文库进行抗菌和抗病毒筛选的组合可以鉴定抗菌和抗病毒领域之一或两者中的不同潜在先导物。根据该I期计划的结果，II期计划涵盖针对I期先导化合物的作用机制和体内功效的研究、文库扩增和先导化合物优化以及包括针对特定寄生虫的筛选。该研究涉及大环内酯类新糖苷的合成及其作为抗菌和抗病毒药物的评价，以确定可开发成有价值的新型抗感染药物的化合物。

DESCRIPTION (provided by applicant): Although it has long been known that macrolide glycosylation is absolutely essential for antibacterial activity, the megalomicins (which differ from erythromycins solely via an additional sugar attached at C6 of the macrolide) were the first macrolides to display notable antiviral and antiparasitic activities. These new activities, unique to the C6-glycosylated macrolides, are proposed to derive from their ability to cause anomalous glycosylation of proteins essential to viral/parasite development. Given the role of macrolide glycosylation in defining the final antibacterial, antiviral and/or antiparasitic potential of this validated drug scaffold, a simple, rapid, robust method to 'glycorandomize' macrolides may launch the discovery of a wide range of anti-infective drug leads. While macrolide semi-synthesis has allowed for the production of a number of second and third generation macrolide analogs, there is an astonishing lack of differentially-glycosylated analogs - due primarily to the severe limitations imposed by classical glycosylation methodologies. The studies proposed in this application are designed to assess the utility of Centrose's patented technology, known as neoglycorandomization, toward this goal. In this Phase I proposal, we will demonstrate the feasibility of creating differentially-glycosylated ketolide libraries for the identification of anti-infective leads via the synthesis and evaluation of two prototype macrolide neoglycoside series. The 'type A' C6 prototype design is based upon a naturally-occurring C6 O-glycoside precedent (megalomicin) with notable antibacterial, antiviral and antiparasitic activities while, the 'type B' C9 prototype design is based upon non-carbohydrate polyether C9-modifications within second generation macrolides (roxithromycin) with notable antibacterial properties. Both prototypes are based upon a ketolide scaffold known as non-inducers of macrolide resistance (e.g. MLSB) and these modifications are anticipated to enhance binding interactions and possibly influence macrolactone rigidity. Fifty prototype A and 50 prototype B analogs will be generated and specifically screened as antibacterials and antivirals. Given the unique activities of megalomicin, it is anticipated that a combination of antibacterial and antiviral screening of the neoglycorandomized prototype libraries proposed may identify distinct potential leads in one, or possibly both, the antibacterial and antiviral arenas. Depending upon the outcome of this Phase I program, a Phase II is envisioned to encompass studies targeting the mechanism of action and the in vivo efficacy of Phase I lead compounds, library expansion and lead optimization as well as the inclusion of screens targeting specific parasites. The research involves the synthesis of macrolide neoglycosides and their evaluation as anti-bacterial and anti-viral agents, to identify compounds that could be developed into valuable new anti-infective drugs.