Development of therapeutic fusion inhibitor peptides for Measles encephalitis

开发治疗麻疹脑炎的融合抑制肽

基本信息

批准号：
10178126
负责人：
Matteo Porotto
金额：
$ 35.44万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10178126
关键词：
Acute Address Animal Model Antiviral Agents Binding Biodistribution Brain C-Peptide C-terminal Cell membrane Cell surface Cells Cellular Immunity Centers for Disease Control and Prevention (U.S.)Central Nervous System Diseases Central Nervous System Infections Cessation of life Child Child Mortality Chimeric Proteins Cholesterol Chronic Complication Data Developed Countries Developing Countries Disadvantaged Disease Disease Outbreaks Encephalitis Encephalomyelitis Evaluation Evolution Fatal Outcome General Population Glycoproteins HIV Hemagglutinin Herd Immunity Home Human Immune Immune response Immune system Immunity Immunocompetent Immunocompromised Host Immunosuppression Impairment In Vitro Incidence Individual Infant Infection Infectious Encephalitis Investigation Lead Life Lipids Lung Measles Measles virus Mediating Membrane Fusion Modeling Mus N-terminal National Institute of Allergy and Infectious Disease Nature Neuraxis Neurons Paramyxovirus Penetration Peptides Periodicity Persons Play Population Pregnant Women Process Publishing Research Risk Role SLAM protein Site Structure Subacute Sclerosing Panencephalitis Tissues Toxic effect Transgenic Mice Treatment Efficacy United States Vaccinated Vaccination Vaccines Viral Virus Virus Diseases Work anti-viral efficacy attenuated measles virus base drug discovery experience fundamental research immunogenicity improved in vitro testing in vivo in vivo evaluation infant infection inhibitor/antagonist lead candidate lead optimization mouse model nectin neglect neutralizing antibody preclinical development pressure prevent prophylactic receptor therapeutic development viral resistance virus envelope virus-induced neurologic disease

Acute Address Animal Model Antiviral Agents Binding Biodistribution Brain C-Peptide C-terminal Cell membrane Cell surface Cells Cellular Immunity Centers for Disease Control and Prevention (U.S.)Central Nervous System Diseases Central Nervous System Infections Cessation of life Child Child Mortality Chimeric Proteins Cholesterol Chronic Complication Data Developed Countries Developing Countries Disadvantaged Disease Disease Outbreaks Encephalitis Encephalomyelitis Evaluation Evolution Fatal Outcome General Population Glycoproteins HIV Hemagglutinin Herd Immunity Home Human Immune Immune response Immune system Immunity Immunocompetent Immunocompromised Host Immunosuppression Impairment In Vitro Incidence Individual Infant Infection Infectious Encephalitis Investigation Lead Life Lipids Lung Measles Measles virus Mediating Membrane Fusion Modeling Mus N-terminal National Institute of Allergy and Infectious Disease Nature Neuraxis Neurons Paramyxovirus Penetration Peptides Periodicity Persons Play Population Pregnant Women Process Publishing Research Risk Role SLAM protein Site Structure Subacute Sclerosing Panencephalitis Tissues Toxic effect Transgenic Mice Treatment Efficacy United States Vaccinated Vaccination Vaccines Viral Virus Virus Diseases Work anti-viral efficacy attenuated measles virus base drug discovery experience fundamental research immunogenicity improved in vitro testing in vivo in vivo evaluation infant infection inhibitor/antagonist lead candidate lead optimization mouse model nectin neglect neutralizing antibody preclinical development pressure prevent prophylactic receptor therapeutic development viral resistance virus envelope virus-induced neurologic disease

展开

项目摘要

Measles (MV) causes disease worldwide despite efforts towards eradication by vaccine, largely because it is spread so readily between people. MV eradication is currently hindered by the endemic nature of MV in developing countries and the decreasing rate of vaccination in developed countries. MV disease is generally self-limited with several life-threatening complications due to the temporary immune suppression and to the central nervous system (CNS) invasion. CNS manifestations following MV infection may occur early after infection, in the case of acute encephalomyelitis. A second form of MV-induced CNS disease, progressive infectious encephalitis, known as measles inclusion body encephalitis (MIBE), occurs in immunosuppressed patients 1 to 6 months after measles infection. This is a lethal sequela that is common in the growing population of immunocompromised patients, who cannot receive or respond to MV vaccination. A third form of MV-induced neurological disease – subacute sclerosing panencephalitis (SSPE) – leads to fatal outcomes years after infection even in the presence of neutralizing antibodies. Data from recent US outbreaks show that the incidence of SSPE can be as high as 1 every 600 infected infants, highlighting the significance of this disease also for the immune competent population. There is no specific therapy for acute or persistent CNS manifestations of measles. We have applied the results of fundamental research to develop a new antiviral strategy for MV CNS infection, based on inhibiting membrane fusion during MV entry. A major impetus for this application is our finding that attachment of lipid moieties to a peptide (termed C-peptide) fusion inhibitor yields three major advantages: (1) increased potency; (2) ability to follow the virus to the site of fusion activation; and (3) CNS penetration. We have shown that our prototypical C-peptide prevents lethal encephalitis in a transgenic mouse model. We propose to assess the therapeutic efficacy of newly improved fusion inhibitory C-peptides. The strategy will be assessed in vitro, ex vivo, and in vivo using wild-type strain MV and CNS adapted strains in immune-compromised mice. The proposed work will address two Specific Aims: 1. To assess the antiviral efficacy of C-peptide fusion inhibitors: in vitro and ex vivo studies. 2. To evaluate therapeutic efficacy of C-peptide fusion inhibitors against MV infection in vivo and to provide the proof of concept for pre-clinical development.

麻疹（MV）导致全球疾病的使命努力，以通过疫苗根除疫苗，主要是因为它很容易在人之间传播。 MV的特有性质目前阻碍了MV的MV 在发展中国家和发达国家的疫苗接种率下降。 MV疾病是由于暂时的免疫抑制和中枢神经系统（CNS）入侵。 MV感染后的中枢神经系统表现可能发生在感染后早期发生，如果是急性脑脊髓炎。 MV诱导的CNS疾病的第二种形式，逐渐感染性脑炎，称为麻疹纳入身体脑炎（MIBE）发生在免疫抑制的患者中1至6个月麻疹感染。这是一个致命的后遗症，在不断增长的人群中很常见无法接受或应对MV疫苗接种的免疫功能低下的患者。 MV诱导的神经系统疾病的第三种形式 - 亚急性硬化脑炎（SSPE） - 即使在存在中和抗体的情况下，感染后几年就会导致致命结局。来自美国最近的疫情表明，SSPE的事件可能高达600名感染婴儿，强调了这种疾病对免疫能力人群的重要性。没有针对麻疹的急性或持续性中枢神经系统表现的特定疗法。我们有应用了基本研究的结果来制定一种新的MV CNS感染抗病毒药策略，基于在MV进入过程中抑制膜融合。我们的发现是该应用程序的主要动力脂质部分的附着在肽（称为C肽）融合抑制剂上的附着会产生三个主要优点：（1）增加效力；（2）能够遵循病毒到融合激活部位的能力；（3）中枢神经系统穿透。我们已经表明，我们的原型C肽可防止A 转基因小鼠模型。我们建议评估新提高融合的治疗效率抑制性C肽。该策略将在体外，离体和体内使用野生型菌株MV评估和中枢神经系统在免疫功能低下的小鼠中适应菌株。拟议的工作将解决两个具体的工作目标： 1。评估C肽融合抑制剂的抗病毒效率：体外和离体研究。 2。评估C肽融合抑制剂对体内MV感染的治疗效率并为临床前开发提供概念证明。