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High-throughput assays and small-molecule discovery of antiviral candidates targeting influenza hemagglutinin

针对流感血凝素的抗病毒候选药物的高通量测定和小分子发现

基本信息

批准号：
10397532
负责人：
IAN A WILSON
金额：
$ 67.85万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
2021-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397532
关键词：
Affinity Animal Model Animals Antibodies Antiviral Agents Appearance Binding Binding Sites Biochemical Biological Assay Biophysics Biotechnology Birds Cells Collection Communities Complementarity Determining Regions Complex Crystallization Cyclic Peptides Development Disease Drug Targeting Economic Burden Epidemic Exhibits Fluorescence Polarization Fluorescence Resonance Energy Transfer Foundations Future Goals Half-Life Head Health Hemagglutinin Housing Human Hydrogen Bonding Hydrophobicity Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H2N2 Subtype Influenza A Virus, H3N2 Subtype Influenza A Virus, H5N1 Subtype Influenza A Virus, H7N7 Subtype Influenza A Virus, H7N9 Subtype Influenza A Virus, H9N2 Subtype Influenza A virus Influenza B Virus Influenza Hemagglutinin Institutes Journals Label Laboratories Lead Libraries Membrane Membrane Glycoproteins Mission Mutation Nature Neuraminidase Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Point Mutation Property Proteins Publishing Reporter Resistance Roentgen Rays Science Serotyping Signal Transduction Site Specificity Structure Surface Surface Antigens United States National Institutes of Health Viral Virus Zoonoses active method anti-influenza base combat combinatorial cost effective design drug discovery feature detection fitness flu fluorophore health economics hemagglutinin I high throughput screening improved influenza infection influenzavirus inhibitor innovation interest iterative design mutant nanomolar neutralizing antibody novel novel therapeutics pandemic disease pandemic influenza pathogenic virus prevent rational design receptor binding scaffold seasonal influenza small molecule small molecule libraries stem stoichiometry therapeutic candidate tool

项目摘要

PROJECT SUMMARY / ABSTRACT Influenza A viruses exhibit extreme diversity as exemplified by the multiple serotypes of the hemagglutinin (HA, H1-H18) and neuraminidase (NA, N1-N11) surface antigens. To date, only 3 of 198 possible combinations of HA and NA in avian and other animal reservoirs have been associated with human pandemics (H1N1, H2N2, H3N2). Recent appearances of H5N1, H6N1, H7N7, H7N9, H9N2, and H10N8 in humans are constant reminders of the potential for devastating new pandemics. Influenza B viruses with its two lineages further increase the health and economic burdens of seasonal influenza. No effective antiviral drugs are currently available for preventing entry of influenza A or B viruses into host cells (scientific premise). However, relatively recent discoveries of broadly neutralizing antibodies to human influenza viruses and concomitant structural studies have identified sites-of-vulnerability on the HA in pandemic, seasonal, and emerging influenza viruses. These HA surface sites include the receptor binding site and membrane-proximal stem housing the fusion machinery, both of which are essential for cellular infection. Common features for recognition of these sites can now be exploited in design of small molecules to ultimately develop broadly applicable influenza antivirals. Here, we will employ this structural information into the optimization and execution of high-throughput assays to identify new small-molecule scaffolds that target the highly conserved and vulnerable stem-binding site. High- throughput screening will be performed in parallel on representative HAs from influenza A group 1 against 600K structurally diverse molecules (SA1). We will also subject group 2 and influenza B HAs to a 300K compound screen (SA2). Validated hit compounds will be prioritized based on affinity and breadth across HAs and top candidates will be rigorously optimized into lead molecules by x-ray structure-based design cycled with medicinal chemistry. Biophysical binding, cellular infectivity and resistance assays (e.g., combinatorial viral libraries of HA mutants) will aid in iterative design, selection, and characterization of potential novel therapeutic candidates with favorable drug-like properties. All of these methods are actively employed in the Wolan and Wilson laboratories. As proof-of-concept for this approach, we identified a molecule with modest affinity to the stem of group 1 HAs with an HT assay of our own design. Its co-crystal structure with HA provided critical information towards design and synthesis of a focused compound library, which we used to produce a stereoselective molecule with nanomolar affinity and antiviral activity. Our overall goal is to identify and improve molecules with broad potency against the stem of groups 1 and 2 as well as flu B HAs. To our knowledge, we are the first to design an assay against group 2 and flu B HAs amenable to HTS (innovation). We anticipate that several classes of stem-targeted compound scaffolds will be identified with nanomolar affinity to HAs with cellular antiviral activity and suitable PK-ADME properties. Future efforts will include animal models of influenza infections to further validate our antivirals with the ultimate goal of combatting future influenza pandemics and seasonal epidemics.

项目摘要/摘要