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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要丝病毒感染了人类，非人类素，蝙蝠和其他哺乳动物。几个丝状病毒人类的出血热疾病，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由于难以确保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新疾病的传播。该项目将揭示靶向糖蛋白（GPS）的新机会通过识别和表征识别和抑制丝状病毒GP的核酸适体。丝状病毒在其表面膜上显示三聚体GP，并在其期间从受感染的细胞中获取集会。 GP是中和和非中和抗体（AB）的结合靶标，以及神经化的分子机制开始出现。但是，不受约束和严重的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（“ GPEBOV”）的情况下，结合位点。较小的配体（例如适体）可能会到达并阻止抗体无法接近的神经表面，它们可以帮助识别新的谈判网站。我们的长期目标是开发适体作为确定新的中和表位的工具，并为在病毒发病机理中解剖分子和细胞事件。当前的建议将确定可行性这种方法并确定机械研究的初始潜在客户。它利用完成参与实验室中病毒学和RNA生物化学方面的专业知识；关于我们最近在高级成就 APATMER选择和信息方法；关于我们最近对机制和多功能性的批判性见解在病毒组装过程中掺入的糖蛋白；并与EBOV添加了新的合作者专业知识。第一个目的将确定适体通过识别GPEBOV和GPMARV之间共享的表位。第二个目标将确定并评估针对已知中和表位的适体。