Document text
Principal Investigator: JULIE M. OVERBAUGH
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2022
Award: $123,360
Funding agency: National Institute of Allergy and Infectious Diseases
The ongoing global pandemic of the novel SARS-CoV-2 coronavirus (CoV) presents an urgent need for development of effective preventative and treatment therapies. The viral-host cell fusion (S) protein spike is a prime target for such therapies owing to its critical role in the virus lifecycle. The S protein is divided into two regions: the N-terminal S1 domain that caps the C-terminal S2 fusion domain. Binding to host receptor via the Receptor Binding Domain (RBD) in S1 is followed by proteolytic cleavage of the spike by host proteases. This leads dramatic conformational transitions resulting in S1 shedding and exposure of the fusion machinery in S2, culminating in host-cell entry. Class I fusion proteins such as the CoV S protein that undergo large conformational changes during the fusion process must, by necessity, be highly flexible and dynamic. Indeed, cryo-EM structures of the SARS-CoV-2 spike reveal considerable flexibility and dynamics in the S1 domain, especially around the RBD that exhibits two discrete conformational states – a “down” state that is shielded from receptor binding, and an “up” state that is receptor-accessible. The overall goals of this study are to use our robust, high-throughput computational and experimental pipeline to define the detailed trajectory of the
“down” to “up” transition of the SARS-CoV-2 S protein, identify early metastable intermediates in the fusion pathway, and exploit their structures and dynamics for identifying drug and vaccine candidates that target SARS-CoV-2. A wealth of structural information on CoV spike proteins, including recently determined cryo-EM structures of the SARS-CoV-2 spike, provides a rich source of detailed data from which to begin precise examination of macromolecular transitions underlying triggering of this fusion machine. The scientific premise of this study is that understanding the structural dynamics and early transition kinetics of mobile regions of the SARS-CoV-2 spike will allow optimal control of vaccine and drug responses, and facilitate the development of novel antiviral drugs and protective vaccines. At the culmination of this study, we expect to have determined structures of multiple “down”, “up”, and intermediate states of the SARS-CoV-2 S protein. Together, these studies will provide important atomically detailed structural and mechanistic information for exploitation in vaccine and therapeutics design.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Amino Acid Sequence><Amino Acids><Antibodies><Antibody Response><Antigenic Determinants><Antiviral Agents><Antiviral Drugs><Antivirals><Assay><Bacteriophages><Binding><Binding Determinants><Bioassay><Biologic Assays><Biological Assay><Blood Plasma><C-terminal><COVID-19><COVID-19 infection><COVID-19 virus><COVID19><COVID19 infection><COVID19 virus><CV-19><CV19><Cell Body><Cell fusion><Cells><Chimera Protein><Chimeric Proteins><Clinical><Clinical Treatment Moab><CoV S protein><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><CoV-2><CoV2><Complement><Complement Proteins><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Coronavirus glycoprotein S><Coronavirus spike protein><Cryo-electron Microscopy><Cryoelectron Microscopy><Data><Development><Diagnostic><Disease><Disorder><Drugs><EBOV><Ebola virus><Ebola-like Viruses><Electron Cryomicroscopy><Epitopes><Esteroproteases><Exhibits><Fusion Protein><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genome><Goals><HIV><HIV Antibodies><HIV-Associated Antibodies><HTLV-III Antibodies><HTLV-III-LAV Antibodies><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Antibodies><Immune><Immune Precipitation><Immunes><Immunoprecipitation><Infection><Kinetics><LAV Antibodies><LAV-HTLV-III><Libraries><Lymphadenopathy-Associated Antibodies><Lymphadenopathy-Associated Virus><MERS><MERS coronavirus disease><MERS-CoV disease><Medication><Methods><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome coronavirus disease><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Monoclonal Antibodies><Mutation><N-terminal><NH2-terminal><Outcome><Pathogenesis><Pathway interactions><Peptidases><Peptide Hydrolases><Peptide Library><Peptides><Phage Display><Phages><Pharmaceutic Preparations><Pharmaceutical Preparations><Plasma><Plasma Serum><Population><Preventative treatment><Preventive treatment><Primary Protein Structure><Process><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><Receptor Protein><Resolution><Reticuloendothelial System, Serum, Plasma><Role><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV2><SARS-CoV2 infection><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Source><Structure><Therapeutic><Therapeutic antibodies><Vaccine Design><Vaccines><Variant><Variation><Viral><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Virus-HIV><Work><Wuhan coronavirus><aminoacid><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antiviral compound><antiviral medication><antiviral therapeutic><bacterial virus><conformation><conformational conversion><conformational state><conformational transition><convalescent plasma><corona virus><corona virus disease 2019><coronavirus S protein><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus spike glycoprotein><cross reactivity><cryo-EM><cryoEM><deep sequencing><design><designing><developmental><drug candidate><drug/agent><ebolavirus><flexibility><flexible><genome mutation><hCoV19><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><mAbs><mutation scanning><mutation screening><nCoV2><neutralizing antibody><novel><pandemic><pandemic disease><pathway><peptide aminoacid sequence><peptide sequence><protein aminoacid sequence><protein sequence><rapid method><rapid technique><receptor><receptor binding><receptor bound><response><severe acute respiratory syndrome-CoV><social role><vaccine antibodies><vaccine candidate><vaccine induced antibodies><vaccine-induced antibodies><virus protein>