Targeting Influenza A Virus by a Carbohydrate-inspired Strategy

通过碳水化合物启发的策略针对甲型流感病毒

• 批准号: 10020313
• 负责人: CHI-HUEY WONG
• 金额: $ 48.38万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020313
• 关键词: Academia; Address; Aluminum Oxide; Antibodies; Antiviral Agents; Applications Grants; Binding; Biology; Capsid Proteins; Carbohydrates; Cell-Mediated Cytolysis; Cells; Cellular Membrane; Clinic; Collaborations; Collection; Complex; Detection; Development; Diagnostic; Drug resistance; Engineering; Event; Genomics; Glass; Glycopeptides; Glycoproteins; HIV; HIV-1; Half-Life; Hemagglutinin; Immune; Immune system; Infection; Influenza; Influenza A virus; Influenza Therapeutic; Libraries; Life Cycle Stages; Malignant Neoplasms; Mediating; Membrane; Methods; Monoclonal Antibodies; Natural Killer Cells; Neuraminidase; Neuraminidase inhibitor; Oligosaccharides; Organism; Oseltamivir; Pathologic; Pharmaceutical Preparations; Play; Polysaccharides; Protein Biosynthesis; Protein Glycosylation; Proteins; Public Health; Research; Research Institute; Resistance; Respiratory System; Risk; Role; Sampling; Slide; Specificity; Structure; Structure-Activity Relationship; Techniques; Technology; Therapeutic; Therapeutic antibodies; Translating; Vaccines; Viral; Viral Hemagglutinins; Viral Proteins; Virus; Virus Diseases; anti-influenza; antibody-dependent cell cytotoxicity; base; cancer cell; clinical development; density; design; drug resistant influenza; effective therapy; human pathogen; improved; in vivo; influenzavirus; intercellular communication; link protein; macrophage; neutralizing antibody; next generation; novel diagnostics; pandemic disease; receptor; receptor binding; recruit; sialic acid receptor; sialylation; tool; zanamivir

PROJECT SUMMARY/ABSTRACT Protein glycosylation and carbohydrate-mediated recognition events play a major role during intercellular communications, which can engage components of the immune system and help maintain a healthy state of the organism. Unfortunately, many viruses can take advantage of protein glycosylation. In the case of influenza virus, the coat protein hemagglutinin (HA) mediates virus binding to sialoside receptors of the host cell and facilitates the fusion of viral and host membranes. Since complex-type N-glycosylation of proteins was shown to be crucial for the influenza virus infectivity, the putative influenza receptor is believed to be a glycoprotein. Unfortunately, N-glycan samples occupy only a small percentage of the established glycan collections that are used in the study of influenza virus. The availability of asymmetrically branched N-glycan samples is instrumental to the development of the next generation diagnostic tools and glycan sequencing methods. Using the modular method developed by our lab, we will expand the current collections of N-glycan structures. In order to improve diagnostic capabilities of glycan arrays for the profiling of influenza strains, we will create N-glycan arrays on the aluminium oxide coated glass (ACG) slides as this technology enables better control over the glycan density and distribution than conventional N-hydroxysuccinimide activated slides; and allows detection of even weak carbohydrate-based interactions. Synthetic samples of N-glycans will be used to optimize the anti-influenza broadly neutralizing antibody FI6, thus assisting clinical development of FI6 as universal and highly potent therapeutics of flu infection. The fragment crystallizable (Fc) region of FI6 contains a single N-glycan at N297, which engage FcγIIIa receptor, thus activating the antibody-depended cell-mediated cytotoxicity (ADCC) mechanism for neutralization and clearance of the infected cells. The current glycan structure-activity relationship (gSAR) is mostly established for the glycoforms with bi-antennary glycans, whereas protein glycoforms containing tetra-antennary complex-type N-glycans have not been accessed yet, even though, increasing the degree of sialylation is expected to improve ADCC and prolong in vivo half-life of glycoprotein therapeutics. We intend to complete the gSAR of FI6 by preparing glycoforms with tri- and tetra-antennary complex-type N-glycans, as well as neuraminidase-resistant N-glycan derivatives. New methods generated by this research and the expanded antibody gSAR will guide the general design of other therapeutic antibodies targeting cancer, HIV-1 and other pathological conditions, and will have a direct impact on public health.

项目总结/文摘