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Principal Investigator: Gavin J Sherlock
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $414,751
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
Emerging and endemic viral pathogens are a persistent threat to human health, the global economy, and national readiness. Viral proteins interact with host proteins to hijack host cells and replicate transmissible viral particles. Human-viral and viral-viral protein-protein interactions (PPls) have been comprehensively characterized for a limited set of viruses, identifying a "PPI profile" for each virus screened. However, these efforts have characterized only a small fraction of the known viruses. A complete viral-human PPI map would be an invaluable resource, enabling analyses of how often interacting viral proteins converge on common human protein targets, cellular functions, or pathways, and which of these interactions are associated with transmissibility or virulence. Combining the viral-human PPI map with human population genetic analyses will enable characterization of the molecular mechanisms underlying extant and ancient epidemics and how these PPIs drive much of human adaptation. In addition, PPI profiles of human viruses could be used to aid screening of animal reservoirs to identify potential threats before a zoonotic spillover occurs. Despite its great promise, characterization of the viral-human PPI map remains a challenge given the throughput of current viral-human PPI screening assays. Current high-throughput assays also lack a quantitative output, meaning that the emergent human-viral PPI map, or viral-viral PPI maps, would be difficult to exploit for important downstream variant scanning or drug screening applications. Here we will use a quantitative sequencing-based protein-protein interaction assay platform to screen for PPls between -24 million viral-human or viral-viral protein pairs. We will further develop this technology into a massively parallel drug screening platform and use it to screen >3 million drug-PPI combinations for small-molecule compounds that promote or antagonize a PPI. The viral-human PPI and drug-PPI maps developed here will be an invaluable resource for a broad research community. In addition, this work will establish new massively parallel and quantitative PPI and drug-PPI screening technologies that will scale with advances in gene synthesis, mutagenesis and sequencing, enabling parallel screening of tens of thousands of gene and gene variants of extant, emerging, and potentially zoonotic viruses.
Terms: <Animals><Anti-viral Agents><Assay><Bar Codes><Bioassay><Biological Assay><Cell Body><Cell Culture Techniques><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Communication><Communities><Complement><Complement Proteins><Cow Pox><Cowpox><DHFR><DHFR gene><Data><Data Set><Dihydrofolate Dehydrogenase><Dihydrofolate Reductase><Drug Screening><Drug Targeting><Drugs><Epidemic><Folic Acid Reductase><Funding><Gene variant><Genes><Genetic analyses><Genetics-Mutagenesis><Grant><HCoV><Health><Hepatitis E><Herpesviridae><Herpesviruses><High Throughput Assay><Human><Infection><Influenza B><Influenza B Virus><Influenza C><Influenza C Virus><Influenza Viruses Type B><Influenza Viruses Type C><Influenzavirus C><Learning><Libraries><Maps><Measures><Medication><Modern Man><Molecular><Mutagenesis><Mutagenesis Molecular Biology><Natural regeneration><ORFs><Open Reading Frames><Orthomyxoviruses Type B><Orthomyxoviruses Type C><Output><Pathway interactions><Pharmaceutical Preparations><Preparedness><Process><Protein Coding Region><Protein Fragment><Protein Interaction Map><Protein-Protein Interaction Map><Proteins><Rabies><Readiness><Regeneration><Research><Research Resources><Resources><Scanning><Subcellular Process><System><Technology><Tetrahydrofolate Dehydrogenase><Variant><Variation><Viral><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virulence><Virus><Water-Borne Hepatitis><Work><Yeasts><Zoonoses><Zoonotic><Zoonotic Infection><allele variant><allelic variant><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><barcode><cell culture><cell cultures><chemical library><complementation><dimer><drug detection><drug testing><drug/agent><gene synthesis><genetic analysis><genetic variant><genome scale><genome-wide><genomewide><genomic variant><herpes virus><high throughput screening><human CoV><human corona virus><human coronavirus><human population genetics><lyssa><particle><pathogenic virus><pathway><protein protein interaction><regenerate><screening><screenings><sequencing platform><small molecule><small molecule libraries><viral pathogen><viral testing><virus pathogen><virus protein><virus testing><yaba><zoonotic spillover>