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 Nipah（NIV）被认为是重要的生物环境风险，又是全球健康风险，具有广泛的，广泛的风险不可预测的大流行潜力。该帕托马病毒的感染是毁灭性的，迅速导致致命脑炎和严重的呼吸道感染。通过空气或食物传播，其感染机制是复杂的，没有药物可以预防或治疗它。最近，我们成功地预防和治疗了NIV 金仓鼠感染。这一成功的关键是我们生物分布研究中令人惊讶的发现，即肽的单一皮下注射可产生足够的抗病毒浓度以实现有效性肺，内皮，最重要的是，在大脑中，由NIV感染靶向的器官，没有任何有毒作用。我们计划使用此信息来开发高效的融合抑制性抗病毒药 Henipaviruses；确定胆固醇偶联的中枢神经系统定位的最佳剂量方案肽；研究对融合抑制剂的抗性机制；并在 NIV疾病的动物模型。我们将应用化学基础研究的结果，基于抑制系统以及中枢神经系统（CNS）的病毒进入。利用这些创新方法和技术，我们将确定开发针对CNS的融合抑制剂的可行性人类使用，还为适用于其他paramyxovires的平台技术奠定了基础治疗其他急性病毒性脑脑。 1