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

• 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
• 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

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）已被公认为是一种重要的生物恐怖风险和全球健康风险，具有广泛的、不可预测的大流行潜力。这种副粘病毒的感染是毁灭性的，迅速引起致命的脑炎和严重的呼吸道感染。NiV通过空气或食物传播，感染机制复杂，目前尚无药物防治，近年来，我们成功地防治了金黄地鼠NiV感染。这一成功的关键是来自我们的生物分布研究的令人惊讶的发现，即肽的单次皮下注射产生足够的抗病毒浓度，以在肺，内皮，最重要的是，在大脑中，NiV感染靶向的器官中有效，而没有任何毒性作用。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的henipaviruses，以确定最佳的剂量方案的中枢神经系统定位胆固醇结合肽，研究耐融合抑制剂的机制，并测试这些假设在动物模型的NiV疾病。我们将应用我们在化学，生物工程和病毒学的基础研究的结果，以抑制病毒进入系统以及在中枢神经系统（CNS）的基础上开发一种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CNS靶向融合抑制剂用于人类的可行性，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：病毒性脑炎正日益引起人们的警觉，最近出现了一系列严重的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引起人类致命脑炎的人畜共患病毒。副粘病毒引起重要的人类疾病，对全球疾病和死亡率有重大贡献。作为本提案主题的人畜共患副粘病毒，即尼帕病毒，由于其致命性脑炎和传染性，是公共卫生的一个紧迫问题。目前提出的抗病毒药物，这可能是有效的减少病毒复制，不能治疗感染的大脑，因为他们不能自由扩散穿过血脑屏障（BBB）。因此，开发能够穿透BBB的抗病毒药物是一个关键的未满足的医疗需求。我们提出了一种策略，通过血脑屏障传递抗病毒药物，以阻断CNS中的病毒感染。