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：
8366672
负责人：
Anne Moscona
金额：
$ 19.36万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-11 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8366672
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 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 West Nile virus 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

DESCRIPTION (provided by applicant): 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 biodistributio 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. PUBLIC HEALTH RELEVANCE: Viral encephalitis is rising as a cause for alarm, with the recent emergence of a series of new agents of serious CNS infection, including West Nile virus, Chikungunya virus, and other zoonotic viruses that cause lethal encephalitis in humans. Paramyxoviruses cause important human illnesses that contribute significantly to global disease and mortality. The zoonotic paramyxovirus that is the subject of this proposal, Nipah virus, is an urgent concern for public health due to its lethal encephalitis and transmissible nature. Current proposed antiviral drugs, which may be effective in reducing viral replication, cannot treat infection in the brain because they cannot freely diffuse across the blood-brain barrier (BBB). The development of antivirals which can penetrate the BBB is therefore a critical unmet medical need. We propose a strategy to deliver an antiviral drug across the BBB to block viral infection in the CNS.

描述（由申请人提供）：尼帕病毒 (NiV) 已被认为是一种重要的生物恐怖风险和全球健康风险，具有广泛且不可预测的大流行潜力。这种副粘病毒的感染具有毁灭性，会迅速引起致命的脑炎和严重的呼吸道感染。它通过空气或食物传播，感染机制复杂，目前尚无预防或治疗药物。最近，我们成功预防和治疗了金黄仓鼠的NiV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即可产生足够的抗病毒浓度，从而在肺、内皮，最重要的是在大脑（NiV 感染的目标器官）中发挥作用，而不会产生任何影响。毒性作用。我们计划利用这些信息来开发针对亨尼帕病毒的高效融合抑制抗病毒药物；确定胆固醇缀合肽中枢神经系统定位的最佳剂量方案；研究融合抑制剂的耐药机制；并在 NiV 疾病动物模型中检验这些假设。我们将应用化学、生物工程和病毒学方面的基础研究成果，开发一种基于抑制病毒进入全身和中枢神经系统（CNS）的新的广谱抗病毒策略。通过利用这些创新方法和技术，我们将确定开发人用中枢神经系统靶向融合抑制剂的可行性，并为适用于其他副粘病毒和治疗其他急性病毒性脑炎的平台技术奠定基础。公共卫生相关性：随着最近出现一系列严重中枢神经系统感染的新病原体，包括西尼罗河病毒、基孔肯雅病毒和其他导致人类致命脑炎的人畜共患病毒，病毒性脑炎正在日益引起人们的警惕。副粘病毒会引起重要的人类疾病，对全球疾病和死亡率产生重大影响。本提案涉及的人畜共患副粘病毒尼帕病毒因其致命性脑炎和传染性而成为公共卫生的迫切关注点。目前提出的抗病毒药物可能可以有效减少病毒复制，但不能治疗大脑感染，因为它们不能自由扩散穿过血脑屏障（BBB）。因此，开发能够穿透血脑屏障的抗病毒药物是一项未得到满足的重要医疗需求。我们提出了一种策略，通过血脑屏障输送抗病毒药物，以阻止中枢神经系统中的病毒感染。