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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.

麻疹（MeV）在世界范围内引起疾病，尽管努力根除