Strain-specific and pan-filoviral aptamer recognition of Ebola virus glycoproteins

埃博拉病毒糖蛋白的菌株特异性和泛丝状病毒适体识别

• 批准号: 9181298
• 负责人: Donald H Burke
• 金额: $ 18.76万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9181298
• 关键词: Achievement; Antibodies; Antiviral Agents; Binding; Binding Sites; Blocking Antibodies; CNTNAP1 gene; Cathepsins; Cells; Chiroptera; Cleaved cell; Data Set; Disease; Disease Outbreaks; Ebola virus; Endosomes; Epitopes; Evaluation; Event; Filovirus; Future; GP2 gene; GTPBP1 gene; Glycoproteins; HIV; Head; Health; Hendra Virus; Hospitals; Human; Infection; Informatics; International; Intervention; Lead; Libraries; Ligands; Mammals; Maps; Membrane; Membrane Fusion; Membrane Glycoproteins; Membrane Proteins; Methods; Molecular; Molecular Conformation; Mucins; Nucleic Acids; Patients; Pharmaceutical Preparations; Polysaccharides; RNA; RNA Biochemistry; Reagent; Recovery; Regimen; Risk; Site; Specificity; Surface; Thermolysin; Vaccines; Viral; Viral Hemorrhagic Fevers; Viral Pathogenesis; Virus; Virus Assembly; Virus Receptors; Western Africa; aptamer; innovation; insight; neutralizing antibody; nonhuman primate; particle; receptor; receptor binding; small molecule; tool; vaccination strategy; virology

Project Summary Filoviruses infect humans, non-human primates, bats and other mammals. Several filoviruses cause hemorrhagic fever diseases in humans, including the recent Ebola virus (EBOV) outbreak in western Africa. Promising interventions are on the horizon, but the need for new strategies is highlighted by the continued absence of an effective and widely-available vaccine or antiviral drug regimen, by the difficulty of assuring patient recovery even in modern hospital settings, and by the continuing risk of the emergence and rapid international spread of new diseases. This project will reveal new opportunities to target glycoproteins (GPs) by identifying and characterizing nucleic acid aptamers that recognize and inhibit filoviral GPs. Filoviruses display a trimeric GP on their surface membrane, which they acquire from infected cells during assembly. GPs are the binding targets for both neutralizing and non-neutralizing antibodies (Ab), and the molecular mechanisms of neutralization are beginning to emerge. However, the non-conserved and heavily- glycosylated mucin-like domain (MLD) blocks Ab access to much of the GP surface, including the NCP1 binding site in the case of EBOV GP (“GPEBOV”). Smaller ligands such as aptamers could potentially reach and block neutralization surfaces that are inaccessible to antibodies, and they could aid identification of new neutralization sites. Our long-term objective is to develop aptamers as tools for identifying new neutralizing epitopes and for dissecting molecular and cellular events in viral pathogenesis. The current proposal will establish feasibility of that approach and identify initial leads for mechanistic studies. It capitalizes on complementary expertise in virology and RNA biochemistry in the participating labs; on our recent achievements in advanced aptamer selection and informatics methods; on our recent critical insights into the mechanisms and versatility of glycoprotein incorporation during viral assembly; and on the addition of new collaborators with EBOV expertise. The first Aim will identify aptamers that neutralize GP-pseudotyped and infectious virus by recognizing epitopes that are shared between (or unique to) GPEBOV and GPMARV. The second Aim will identify and evaluate aptamers that target known neutralizing epitopes.

项目摘要 丝状病毒感染人类，非人类灵长类动物，蝙蝠和其他哺乳动物。 人类的出血热疾病，包括西非最近的埃博拉病毒（EBOV）爆发。 有希望的干预措施即将到来，但是持续的新策略的需求突出了 通过分配的差异，没有有效且广泛可用的疫苗或抗体药物方案 即使在现代医院环境中，患者康复，以及出现的持续风险和快速的风险 国际疾病的传播。 通过识别并识别识别甲氮的FILOVIRAL GPS的核化适体。 丝状病毒在其表面膜上显示三聚体GP，它们从受感染的细胞中获取 组装是中和的目标 中和的分子机制开始出现。 糖基化的粘蛋白样结构域（MLD）阻止AB进入大部分GP表面，包括NCP1 在EBOV GP的情况下（“ GPEBOV”）绑定位点。 并阻塞中和表面，这是不可接受的，它们可以帮助有助于帮助 新的中和。 我们的长期目标是建立适当的选择，以确定新的中和表位和 病毒发病机理中的分子和细胞事件。 用于机械研究的热门方法和初始潜在客户。 参与实验室中病毒学和RNA生物化学方面的专业知识） 适中的选择和信息学方法； 在病毒组装期间的糖蛋白掺入； 专业知识。 认识到GPEBOV和GPMARV之间共享的表位。 和靶向已知中和表位的评估适体。