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：
10457081
负责人：
Matteo Porotto
金额：
$ 56.12万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-09 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457081
关键词：
2019-nCoV Acute Address Amnesia Animal Model Animals Antiviral Agents Biodistribution C-terminal Canine Distemper Virus Canis familiaris Cell membrane Cells Cellular Immunity Central Nervous System Infections Chemical Engineering Child Childhood Chimeric Proteins Clinical Communicable Diseases Complex Complication Cytoplasm Data Disease Disease Outbreaks Encephalitis Engineering Epithelial Cells Ethics Ferrets Fetus General Population Genome Glycoproteins Grant Hemagglutinin Hospitalization Hydrophobicity Immune Immune system Immunocompromised Host Immunosuppression Impairment In Vitro Individual Infant Infection Infection prevention Interruption Intranasal Administration Kinetics Lead Lipids Lymphoid Cell Measles Measles virus Measures Mediating Medical Membrane Membrane Fusion Modeling Molecular Conformation Morbillivirus Morbillivirus Infections Mothers Movement Myeloid Cells N-terminal National Institute of Allergy and Infectious Disease Neurologic Nucleoproteins Paramyxovirus Pathogenesis Peptides Periodicity 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 Structure Testing Toxic effect Translating United States Vaccinated Vaccination Vaccines Vertical Disease Transmission Viral Viral Load result Virus Virus Diseases Vision Work attenuated measles virus base biophysical analysis design dimer fundamental research human disease in vitro testing in vivo inhibitor/antagonist low income country mortality nanoparticle nectin nonhuman primate pre-exposure prophylaxis preclinical development prevent receptor self assembly social transmission process viral entry inhibitor 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 today, mainly due to social issue (e.g., antivaxxer movement), eradication is not in sight. The recent resurgence of measles in the U.S. highlights the need of effective measure to prevent host-to-host transmission at the moment of the outbreak surge. We have applied the results of fundamental research to develop a new antiviral strategy for MeV, based on inhibiting membrane fusion during MeV entry. This application will test whether our antiviral approach prevents inter-host transmission and therefore fill this medical demand. Our strategy is based MeV fusion inhibitors (i.e., lipid conjugated peptides) that self-assemble in stable nanoparticles until they reach the target cells were, they integrated into the cell membrane. We have recently shown that this strategy works effectively for SARS-CoV-2. We propose to chemical engineer these inhibitors to optimize 1) the antiviral potency, 2) the conditions under which the peptides self-assemble, 3) the insertion on the target cell membrane, and 5) 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。与今天一样，主要由于社会问题（例如反疫苗运动），根除疫苗尚未完成视线。最近麻疹在美国再次流行，凸显了有效治疗的必要性。疫情爆发时防止宿主间传播的措施。我们应用基础研究成果来开发新的抗病毒策略对于MeV，基于MeV进入期间抑制膜融合。该应用程序将测试我们的抗病毒方法是否可以防止主机间传播，因此填写此内容医疗需求。我们的策略是基于 MeV 融合抑制剂（即脂质缀合肽）在稳定的纳米粒子中自组装，直到到达靶细胞是，它们整合到细胞膜中。我们最近证明这一策略对 SARS-CoV-2 有效。我们建议对这些抑制剂进行化学改造，以优化 1) 抗病毒效力，2) 肽自组装的条件，3) 插入靶细胞膜，5) 体内生物分布。我们的工作将使用麻疹病毒的天然模型进行体外、离体和体内测试感染（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。