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.

尽管麻疹（MEV）仍在全球引起疾病疫苗，很大程度上是因为它很容易在人之间传播。急性MEV感染引起免疫性健忘症，导致对其他感染性的敏感性增加疾病。另外，罕见但严重的神经系统并发症可能会发展出几种由于中枢神经系统的持续性MEV感染导致麻疹几年。细胞免疫力受损的人有增加严重的风险麻疹，但通常无法接种疫苗，因为疫苗病毒本身可能导致致命疾病。没有针对MEV表现的特定疗法。一个成功的疫苗接种运动本可以在20年前消除MEV。截至目前，根除尚未视线和麻疹的复兴2019年强调需要采取有效措施以防止在爆发的时刻。我们最近描述了一种新的MEV特异性融合结合病毒特异性靶向，自组装和细胞的抑制剂肽膜整合导致MEV融合抑制剂的表现优于我们以前的体外和体内融合抑制剂。该应用程序将测试该新抑制剂是否防止宿主间传播，因此满足了这一医疗需求。我们建议化学工程师这些抑制剂以优化1）病毒特异性靶向，2）插入感染细胞膜，3）体内生物分布。我们的工作将是在体外测试，体内和体内使用天然的虫比病毒感染模型（犬蒸发病毒-CDV-在雪貂中）。 1。使用蛋白质工程来优化自组装特性和 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 CDV在体内感染，并为临床前开发提供了概念证明。