Carbohydrate-based Antiinfective Agents

碳水化合物类抗感染剂

基本信息

批准号：
7471431
负责人：
CHI-HUEY WONG
金额：
$ 44.72万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7471431
关键词：
Adjuvant Agonist Anabolism Anti-Bacterial Agents Anti-Infective Agents Antibiotic Resistance Antiviral Agents Area Avian Influenza Bacteria Binding Biological Assay Biological Process Birds Carbohydrates Cell Wall Cell surface Cells Chemistry Complex Data Development Drug resistance Elements Enzymes Epitopes Future Glycolipids Hemagglutinin Human Immune response Immunosuppressive Agents Immunotherapeutic agent In Situ Infection Influenza A Virus, H5N1 Subtype Intervention Investigation Libraries Ligands Lipids Methodology Molecular Target Monobactams Mus Neuraminidase Neuraminidase inhibitor New Agents Peptidoglycan Peptidyltransferase Process Reaction Regulation Research Role Screening procedure Sialic Acids Specificity Structure Structure-Activity Relationship Variant Viral Proteins Virulent Virus Virus Diseases Work analog base cytokine design drug development experience high throughput screening improved influenzavirus inhibitor/antagonist novel novel strategies prevent programs receptor response selectfluor

项目摘要

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.

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正在出现的靶点的抗感染剂，这些靶点在其作用机制中识别或处理碳水化合物结构域。细菌和病毒耐药菌株的不断出现不仅需要基于已确定的分子靶点开发新药物，更重要的是需要研究尚未用于药物开发的新靶点。该提案描述了三个主要研究领域。第一个是针对细菌转糖基酶，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，但人们对转糖基酶仍知之甚少，这主要是因为难以获得其脂质 II 底物，并且缺乏高通量测定。我们将利用表达这种酶的经验以及脂质 II 和相关类似物的合成经验来开发高通量测定并详细研究转糖基反应的结构决定因素。这项工作的结果将用于设计潜在抑制剂库，利用我们在基于微量滴定的化学和原位筛选方面的最新进展来快速获得抑制剂。第二个领域是针对流感病毒神经氨酸酶和血凝素。我们将利用我们的氟糖苷合成方法来开发针对两种病毒蛋白的双功能抑制剂。我们将与我们的合作者伊恩·威尔逊 (Ian Wilson) 一起重点研究新毒力禽流感病毒株中 HA 的碳水化合物特异性。第三个领域将靶向 CD1d 来激活 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。利用我们的合成方法，我们和我们的合作者将继续开发改进的 CD1d 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禽流感等新出现的病毒对全球构成了重大威胁。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疗法来治愈和预防它们。