novel macrolides as anti-infective drugs

新型大环内酯类抗感染药

• 批准号: 7323549
• 负责人: charles r hutchinson
• 金额: $ 24.41万
• 依托单位: CENTROSE, LLC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7323549
• 关键词: Acquired Immunodeficiency Syndrome; Amino Sugars; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics; Antiparasitic Agents; Antiviral Agents; Bacillus anthracis; Binding; Brucella; Burkholderia mallei; Carbohydrates; Categories; Communities; Deoxy Sugars; Development; Disaccharides; Enteral; Erythromycin; Evaluation; Generations; Glycosides; Goals; HIV; Haemophilus influenzae; Hepatitis; Hepatitis C virus; Infectious Agent; Ketolides; Lead; Legal patent; Libraries; Macrolide-resistance; Macrolides; Methodology; Methods; Modification; Moraxella (Branhamella) catarrhalis; Muscle Rigidity; New York; Numbers; Outcome; Parasites; Pharmaceutical Preparations; Phase; Production; Property; Protein Glycosylation; Range; Reporting; Research; Respiratory System; Role; Route; Roxithromycin; Screening procedure; Series; Services; Streptococcus pneumoniae; Technology; Vibrio cholerae; Viral; Virus; Yersinia pestis; analog; base; design; drug discovery; glycosylation; in vivo; megalomicin A; member; novel; pathogen; programs; prototype; respiratory; scaffold; sugar; thiosugar; virology

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.

说明书(申请人提供)：虽然人们早就知道大环内酯糖基化对抗菌活性是绝对必要的，但大环霉素(仅通过大环内酯C6上附加的糖而不同于红霉素)是第一个显示出显著抗病毒和抗寄生虫活性的大环内酯类化合物。这些新的活性是C6糖基化大环内酯所特有的，被认为是因为它们能够导致病毒/寄生虫发育所必需的蛋白质的异常糖基化。鉴于大环内酯糖基化在确定这种经过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、稳健的大环内酯糖随机化方法可能会启动广泛的抗感染药物先导的发现。虽然大环内酯半合成方法已经可以生产一些第二代和第三代大环内酯类似物，但令人惊讶的是缺乏差异糖基化类似物-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，即所谓的新糖随机化，对这一目标的实用性。在这个第一阶段的提案中，我们将通过两个大环内酯新糖苷系列原型的合成和评价来证明创建差异糖基化酮内酯文库用于鉴定抗感染先导化合物的可行性。A类C6原型设计基于自然产生的具有显著抗菌、抗病毒和抗寄生虫活性的C6O-糖苷先例(Megalomicin)，而B类C9原型设计基于具有显著抗菌特性的第二代大环内酯类化合物(罗红霉素)中的非碳水化合物聚醚C9修饰。这两个原型都是基于一种被称为大环内酯耐药非诱导剂的酮内酯支架(例如MLSB)，这些修饰有望增强结合相互作用，并可能影响大内酯的刚性。将产生50个原型A和50个原型B类似物，并专门筛选为抗菌和抗病毒药物。鉴于Megalomicin的独特活性，预计对所提出的新糖随机化原型文库进行抗菌和抗病毒联合筛选可能在抗菌和抗病毒领域中的一个或两个领域识别出不同的潜在线索。根据这一第一阶段计划的结果，预计第二阶段将包括针对第一阶段先导化合物的作用机制和体内有效性的研究，文库扩大和铅优化，以及包括针对特定寄生虫的筛选。本研究涉及大环内酯类新糖苷类化合物的合成及其作为抗细菌和抗病毒药物的评价，以确定可开发为有价值的抗感染新药的化合物。