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Targeting glycoprotein (G) domain-III for pan-lyssavirus nanobody therapeutics

靶向糖蛋白 (G) 结构域 III 用于泛狂犬病病毒纳米抗体治疗

基本信息

批准号：
10667756
负责人：
Kai Xu
金额：
$ 22.82万
依托单位：
OHIO STATE UNIVERSITY
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：
2023-03-07 至 2023-11-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10667756
关键词：
Acute Adopted Affect Affinity Antibodies Antigen-Antibody Complex Antigenic Diversity Antigens Bacteriophages Binding Biochemical Biological Assay Camels Central Nervous System Cessation of life Clinical Communicable Diseases Development Disease Disease Progression Dose Electron Microscopy Encephalitis Epitopes Family Future GTP-Binding Proteins Generations Genetic Variation Glycoproteins Homologous Protein Human Immune Immunize Immunoglobulins Immunotherapeutic agent Libraries Lyssavirus Mammals Maps Modality Modeling Molecular Conformation Monoclonal Antibodies PH Domain Persons Phage Display Prophylactic treatment Proteins Rabies Rabies Vaccines Reporting Rhabdoviridae Sequence Analysis Site Structure Surface Tertiary Protein Structure Therapeutic Therapeutic Agents Therapeutic antibodies Vaccines Viral Virion Virus X-Ray Crystallography Zoonoses design design and construction extracellular flexibility glycoprotein G human monoclonal antibodies improved in vivo member mouse model nanobodies neutralizing antibody novel prevent protective efficacy protein structure screening segregation structural biology therapeutically effective

项目摘要

Abstract The lethal rabies encephalitis diseases are caused by members of the zoonotic lyssavirus genus. The high genetic diversity separates lyssavirus members into three phylogroups, while cross-phylogroup (especially to phylogroups 2 and 3) protection has not been established by current post-exposure prophylaxis (PEP) or antibody therapeutics. To achieve more broadly effective countermeasures to rabies disease worldwide and to prepare for the emergence of new lyssaviruses, effective therapeutic agents against all phylogroups are necessary. Lyssavirus G glycoprotein is the sole antibody target on the virion surface, which adopt distinct conformations between pre- and post- fusion states as other class-III viral fusion machineries. Domain-III of lyssavirus G glycoprotein encompasses a large neutralizing antibody-accessible surface in the native state. Sequence analysis on domain-III revealed several conserved patches across all phylogroups, which could potentially serve as target epitopes for pan-lyssavirus neutralizers. Antigen-specific nanobodies have been considered as promising therapeutic agents against various infectious diseases and non-infectious diseases, which have the advantage in binding compact and hidden epitopes that are out of reach for conventional antibodies. We hypothesized that by focusing immune recognition on the lyssavirus G domain-III conserved epitopes, we can identify pan-lyssavirus neutralizing nanobodies for immunotherapeutics. In this study, we propose two specific aims: (1) to use a structure-based and antibody-guided approach to design and characterize the antigenicity of lyssavirus glycoprotein domain-III, a site of viral vulnerability targeted by several broadly neutralizing antibodies, for revelation of the antibody neutralization mechanism; (2) to identify and characterize pan-lyssavirus neutralizing nanobodies for therapeutics by focusing immune recognition on lyssavirus G domain III conserved epitopes.

摘要