Carbohydrate-based Antiinfective Agents

描述（由申请人提供）：拟议的研究计划旨在开发作用于新的或新兴靶标的抗感染药物，这些靶标在其作用机制中识别或处理碳水化合物结构域。细菌和病毒的耐药菌株的不断出现不仅保证了基于已建立的分子靶点的新药剂的开发，而且更重要的是还没有被开发用于药物开发的新靶点的研究。该提案描述了三个主要研究领域。第一个是靶向细菌转糖基酶，这是参与细胞壁肽聚糖组装的酶功能之一。虽然转肽酶早已被确定为β-内酰胺抗生素的靶标，但转糖基酶仍然知之甚少，主要是因为难以获得其脂质II底物，以及缺乏高通量测定。我们将利用我们在表达这种酶方面的经验，以及我们在Lipid II和相关类似物方面的合成经验，开发高通量检测方法，并详细研究转糖基化反应的结构决定因素。这项工作的结果将被用来设计潜在的抑制剂库，利用我们最近的发展，在微量滴定为基础的化学原位筛选，以快速访问抑制剂。第二个领域是针对流感病毒的神经氨酸酶和血凝素。我们将使用我们的方法合成的氟糖苷开发双功能抑制剂，目标是两种病毒蛋白。与我们的合作者，伊恩威尔逊，我们将集中在碳水化合物特异性的HA从强毒的新禽流感毒株。第三个领域将靶向CD 1d以激活NKT细胞，这是一种有前途的干预细菌和病毒感染的新方法。与我们的合作者Ian Wilson和Moriya Tsuji一起，我们已经开始了解糖基神经酰胺配体选择性激活佐剂或免疫抑制反应的结构基础。使用我们的合成方法，我们和我们的合作者将继续开发改进的CD 1d激动剂，并确定这些化合物在治疗细菌和病毒感染方面的潜力。抗生素耐药性感染和新出现的病毒，如禽流感，构成了重大的全球威胁。我们的研究旨在发现对抗这些感染的新方法，并将在未来产生有效的新治疗方法来治愈和预防它们。

DESCRIPTION (provided by applicant): The proposed research program aims to develop antiinfective agents that act on new or emerging targets, which recognize or process carbohydrate domains in their mechanism of action. The continuing emergence of drug-resistant strains of both bacteria and viruses warrants not only the development of new agents based on established molecular targets, but more importantly the investigation of new targets that have not yet been exploited for drug development. The proposal describes three main areas of research. The first is targeting the bacterial transglycosylase, one of the enzymatic functionalities involved in the assembly of the cell wall peptidoglycan. While the transpeptidase has long been established as the target of p-lactam antibiotics, the transglycosylase remains poorly understood, largely because of the difficulty of accessing its Lipid II substrate, and the lack of a high throughput assay. We will use our experience in expressing this enzyme, and our synthetic experience with Lipid II and related analogues, to develop a high-throughput assay and study in detail the structural determinants of the transglycosylation reaction. Results of this work will be used to design libraries of potential inhibitors, taking advantage of our recent developments in microtiter-based chemistry an in situ screening to rapidly access inhibitors. The second area is targeting the influenza virus neuraminidase and hemagglutinin. We will use our methodology for synthesis of fluoroglycosides to develop bifunctional inhibitors that target both viral proteins. With our collaborator, Ian Wilson, we will focus on the carbohydrate specificity of HA from virulent new avian flu strains. The third area will target CD1d for activation of NKT cells, which is a promising new approach to intervention in both bacterial and viral infections. With our collaborators Ian Wilson and Moriya Tsuji, we have begun to understand the structural basis for selective activation of adjuvant or immunosuppressive responses by glycosylceramide ligands. Using our synthetic methodology, we and our collaborators will continue to develop improved CD1d agonists and define the potential these compounds have in treating bacterial and viral infections. Antibiotic-resistant infections and emerging viruses such as the avian flu pose a significant worldwide threat. Our research aims to discover new ways to combat these infections, and will result in effective new treatments to cure and prevent them in the future.