Design of fusion inhibitors to block measles host-to-host infection

设计融合抑制剂来阻止麻疹宿主间感染

基本信息

批准号：
10753711
负责人：
Matteo Porotto
金额：
$ 73.69万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753711
关键词：
Acute Amnesia Animal Model Animals Antiviral Agents Area Attenuated Biodistribution Canine Distemper Virus Cell membrane Cells Cellular Immunity Central Nervous System Infections Chemical Engineering Child Chimeric Proteins Clinical Communicable Diseases Complex Cytoplasm Data Disease Disease Outbreaks Encephalitis Engineering Epithelial Cells Ethics Ferrets Fetus General Population Genome Grant Hemagglutinin Hospitalization Hydrophobicity Immune Immune system Immunocompromised Host Immunosuppression Impairment In Vitro Individual Infant Infection Infection prevention Interruption Intranasal Administration Kinetics Lipids Lung Lymphoid Cell Measles Measles Vaccine Measles virus Measures Mediating Medical Medical center Membrane Membrane Glycoproteins Modeling Molecular Conformation Morbidity - disease rate Morbillivirus Morbillivirus Infections Mothers Myeloid Cells N-terminal National Institute of Allergy and Infectious Disease Neurologic Nucleoproteins Paramyxovirus Pathogenesis Peptides Periodicals Permeability Persons Play Pneumonia Predisposition Pregnant Women Primates Property Protein Engineering Proteins RNA RNA-Directed RNA Polymerase Recombinants Reporter Reporting Research Ribonucleoproteins Risk Rodent Role SLAM protein Site Testing Toxic effect Translating United States Vaccinated Vaccination Vaccines Vertical Transmission Viral Viral Physiology Virus Virus Diseases Virus Replication Work airway epithelium conformational conversion design dimer efficacy evaluation efficacy study human disease immunogenicity improved in vitro testing in vivo inhibitor low and middle-income countries mortality nanoparticle nectin nonhuman primate outbreak control pre-exposure prophylaxis preclinical development prevent receptor self assembly transmission process viral transmission

项目摘要

Measles (MeV) causes disease worldwide despite efforts towards eradication by vaccine, largely because it is spread so readily between people. Acute MeV infection causes immune amnesia, resulting in increased susceptibility to other infectious diseases. In addition, rare but severe neurological complications can develop several years after measles due to persistent MeV infection of the central nervous system. People with impaired cellular immunity are at increased risk of developing severe measles, but often cannot be vaccinated since the vaccine virus itself can lead to fatal illness. There is no specific therapy for acute or persistent MeV manifestations. A successful vaccination campaign could have eradicated MeV more than 20 years ago. As of today, eradication is not in sight and the resurgence of measles in the U.S. 2019 highlights the need for effective measures to prevent host-to-host transmission at the moment of the outbreak surge. We have recently described a new MeV-specific fusion inhibitor peptide that combines viral-specific targeting, self-assembling, and cell- membrane integration leading to a MeV fusion inhibitor that outperformed our previous fusion inhibitors in vitro and in vivo. This application will test whether this new inhibitor prevents inter-host transmission and therefore fill this medical demand. We propose to chemical engineer these inhibitors to optimize 1) the viral-specific targeting, 2) the insertion on infected cells membrane, and 3) in vivo biodistribution. Our work will be tested in vitro, ex vivo, and in vivo using a natural model of morbillivirus infection (Canine Distemper Virus -CDV- in Ferrets). 1. To use protein engineering to optimize the self-assembling properties and antiviral potency of HRC-peptide fusion inhibitors. 2. To evaluate the protection afforded by HRC peptide fusion inhibitors against CDV infection in vivo and provide proof of concept for pre-clinical development.

尽管努力根除麻疹 (MeV)，但它仍会在全世界范围内引发疾病疫苗，很大程度上是因为它很容易在人与人之间传播。急性MeV感染导致免疫失忆，导致对其他传染病的易感性增加疾病。此外，罕见但严重的神经系统并发症可能会出现多种由于中枢神经系统持续感染 MeV，导致麻疹发生数年后。细胞免疫受损的人患严重疾病的风险增加麻疹，但通常不能接种疫苗，因为疫苗病毒本身可导致致命疾病。目前没有针对急性或持续性 MeV 表现的具体治疗方法。一个成功的疫苗接种运动本可以在 20 多年前根除 MeV。截至目前，根除麻疹仍遥遥无期，2019 年美国麻疹卷土重来强调需要采取有效措施来防止主机间的传播爆发激增的时刻。我们最近描述了一种新的 MeV 特定融合结合了病毒特异性靶向、自组装和细胞- 膜整合导致 MeV 融合抑制剂的性能优于我们之前的体外和体内融合抑制剂。该应用程序将测试这种新抑制剂是否防止宿主间传播，从而满足这一医疗需求。我们建议对这些抑制剂进行化学工程设计以优化 1) 病毒特异性靶向，2) 插入受感染细胞膜上，3) 体内生物分布。我们的工作将是使用麻疹病毒感染的自然模型（犬雪貂中的犬瘟热病毒 -CDV-）。 1. 利用蛋白质工程优化自组装特性并 HRC-肽融合抑制剂的抗病毒效力。 2. 评估 HRC 肽融合抑制剂提供的保护作用 CDV 体内感染并为临床前开发提供概念证明。