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Design of CNS-targeted peptide entry inhibitors for emerging henipaviruses

针对新兴亨尼帕病毒的中枢神经系统靶向肽进入抑制剂的设计

基本信息

批准号：
9251618
负责人：
Anne Moscona
金额：
$ 44.86万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2016-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251618
关键词：
Acute Address Air Amino Acid Substitution Animal Model Animals Antiviral Agents Asia Back Binding Biodistribution Biomedical Engineering Blood - brain barrier anatomy Brain C-terminal Cell fusion Cell membrane Cells Cellular Membrane Central Nervous System Infections Cercopithecus pygerythrus Chemistry Chikungunya virus Cholesterol Complex Coupled Development Diffuse Disease Dominant-Negative Mutation Dose Drug Kinetics Effectiveness Encephalitis Endothelium Event Evolution Food Hendra Virus Henipavirus Human In Vitro Infection Laboratories Lead Lung Mediating Medical Membrane Membrane Fusion Membrane Glycoproteins Mesocricetus auratus Modeling Molecular Mutagenesis N-terminal Nature Neuraxis New Agents Nipah Virus Organ Paramyxovirus Penetration Peptides Pharmaceutical Preparations Pharmacodynamics Phase Play Process Property Protein Engineering Public Health Regimen Resistance Respiratory Tract Infections Risk Role Security Series Staging Structure Subcutaneous Injections Surface Systems Analysis Technology Terminal Repeat Sequences Testing Therapeutic Time Toxic effect Transmembrane Domain Treatment Efficacy Viral Viral Encephalitis Viral Fusion Proteins Virion Virus Virus Diseases Virus Replication West Nile virus abstracting base biodefense design effective therapy functional group fundamental research global health inhibitor/antagonist innovation mortality nervous system disorder neurotropic nonhuman primate novel therapeutics pandemic disease pathogen prevent programs research study resistance mechanism success tool virology

项目摘要

Abstract Nipah (NiV) has been recognized as both an important bioterror risk and a global health risk with broad, unpredictable pandemic potential. Infection from this paramyxovirus is devastating, rapidly causing lethal encephalitis and serious respiratory infections. Transmitted by air or food, its mechanism of infection is complex, and no drugs exist to prevent or treat it. Recently, we have successfully prevented and treated NiV infection in golden hamsters. Key to this success is the surprising finding from our biodistribution studies, that a single subcutaneous injection of the peptide generates sufficient antiviral concentrations for effectiveness in the lung, endothelium and, most importantly, in the brain, the organs targeted by NiV infection, without any toxic effect. We plan to use this information to develop highly effective fusion-inhibitory antivirals for henipaviruses; to determine the optimal dose regimens for CNS localization of cholesterol-conjugated peptides; to investigate the mechanisms of resistance to fusion inhibitors; and to test these hypotheses in animal models of NiV disease. We will apply the results of our fundamental research in chemistry, bioengineering and virology to the development of a new broad-spectrum antiviral strategy based on inhibiting virus entry systemically as well as in the central nervous system (CNS). By utilizing these innovative approaches and technologies, we will determine the feasibility of developing CNS-targeted fusion inhibitors for human use, and also set the stage for a platform technology applicable to other paramyxoviruses and for the treatment of other acute viral encephalitides. 1

抽象的尼帕病毒 (NiV) 已被认为是一种重要的生物恐怖风险和广泛的全球健康风险。不可预测的大流行潜力。这种副粘病毒的感染具有毁灭性，可迅速导致致命脑炎和严重呼吸道感染。通过空气或食物传播，其感染机制是复杂，并且没有药物可以预防或治疗它。最近，我们成功预防和治疗NiV 金仓鼠感染。这一成功的关键是我们的生物分布研究中令人惊讶的发现，即单次皮下注射该肽可产生足够的抗病毒浓度，以有效发挥作用肺、内皮，最重要的是，大脑，即 NiV 感染的目标器官，没有任何毒性作用。我们计划利用这些信息来开发高效的融合抑制抗病毒药物亨尼帕病毒；确定胆固醇结合物中枢神经系统定位的最佳剂量方案肽；研究融合抑制剂的耐药机制；并检验这些假设 NiV 疾病的动物模型。我们将应用化学基础研究的成果，生物工程和病毒学开发基于抑制的新的广谱抗病毒策略病毒进入全身以及中枢神经系统（CNS）。通过利用这些创新方法和技术，我们将确定开发中枢神经系统靶向融合抑制剂的可行性人类使用，也为适用于其他副粘病毒的平台技术和治疗其他急性病毒性脑炎。 1