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

• 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
• 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

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.

麻疹（MeV）在世界范围内引起疾病，尽管人们努力根除麻疹， 疫苗，主要是因为它很容易在人与人之间传播。急性MeV感染 导致免疫健忘症，从而增加对其他感染性疾病的易感性。 疾病此外，罕见但严重的神经系统并发症可能会发展成几种 由于中枢神经系统的持续MeV感染，麻疹后10年。 细胞免疫力受损的人患严重的 麻疹，但往往不能接种疫苗，因为疫苗病毒本身可导致致命的 病对于急性或持续性MeV表现没有特异性治疗。一 成功的疫苗接种运动可以在20多年前消除MeV。 今天，主要是由于社会问题（例如，antivaxxer运动），根除不是在 视线最近在美国麻疹的复苏强调了有效的预防措施的必要性。 在疫情激增时采取措施防止宿主到宿主的传播。 我们已经应用基础研究的结果来开发新的抗病毒策略 对于MeV，基于在MeV进入期间抑制膜融合。此应用程序将 测试我们的抗病毒方法是否可以防止宿主间的传播， 医疗需求。我们的策略是基于MeV融合抑制剂（即，脂质缀合 肽）在稳定的纳米颗粒中自组装，直到它们到达靶细胞 它们被整合到细胞膜中。 我们最近证明，这种策略对SARS-CoV-2有效。 我们建议对这些抑制剂进行化学工程改造，以优化1）抗病毒效力，2） 肽自组装的条件，3）插入靶细胞 膜，和5）体内生物分布。 我们的工作将在体外，离体，和使用麻疹病毒的天然模型在体内进行测试 感染（犬瘟热病毒-CDV-在雪貂）。 1.利用蛋白质工程优化自组装特性， HRC-肽融合抑制剂的抗病毒功效。 2.为了评估HRC肽融合抑制剂提供的保护， CDV体内感染，并为临床前开发提供概念验证。