Document text
Principal Investigator: Dennis R. Burton
Organization: SCRIPPS RESEARCH INSTITUTE, THE
Fiscal Year: 2021
Award: $635,619
Funding agency: National Institute of Allergy and Infectious Diseases
Coronaviruses (CoVs) are enveloped, positive-sense, single-stranded RNA viruses and are divided into Alphaand Beta-coronaviruses. CoVs infect mammals and birds and typically result in lower and/or upper respiratory tract disease. The spectrum of illness in humans caused by CoVs range from common colds to worldwide epidemics/pandemics, including severe acute respiratory syndrome (SARS-CoV) in 2003, human CoV-NL63 in 2004, human CoV-HKU1 in 2005, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, and SARS-CoV-2 in 2019. There are no approved vaccines or antiviral drugs to combat CoV infections and a lack of
tested and validated therapeutics represents a tremendous global concern with respect to the current SARSCoV-2 outbreak.
At the end of December 2019, the World Health Organization became aware of an abnormally large cluster of pneumonia cases localized in the city of Wuhan, China. Within a span of only 3 months, over one million confirmed cases of COVID-19 have been diagnosed worldwide with almost 50,0000 resulting in death. The numbers in the US are now growing at an alarming rate (currently ~25% of the global total) as well as the number
of deaths (currently ~10% of total). The severity of human CoV infections and high mortality rates were strikingly apparent in 2002 with the first SARS-CoV pandemic in Guangdong, China, as well as the MERS-CoV outbreak in 2012. Like SARS-CoV, the current SARS-CoV-2, which is 79% identical, also employs angiotensin converting enzyme II (ACE2) as the host receptor for cellular entry. The CoV surface-exposed spike (S) protein is responsible for the recognition and binding of ACE2 and represents a potential target for development of vaccines and antiviral therapeutics. Importantly, antibodies (Abs) isolated to date from COVID-19 patients appear to bind several regions on the spike protein that then represent ideal targets for small molecule discovery.
The spike protein on the CoV surface is a glycosylated trimer and consists of two extracellular domains, S1 and S2. The majority of nAbs (neutralizing Abs) to CoVs characterized to date target the S1 domain that contains the receptor-binding domain (RBD) responsible for ACE2 binding. Notwithstanding, Abs with epitopes on the S2 domain, consisting of the stem fusion machinery, also have neutralizing potential in both cell-based and animal models of infection and are generally more broadly reactive against other CoVs than those antibodies that target
S1. Additionally, a helical peptide EK1 derived from the HR2 domain of human CoV-OC43 (a strain responsible for the common cold) broadly binds to the stem region of CoVs and inhibits membrane fusion. Our goal with this supplement is to define the neutralizing epitopes on the S protein of SARS-CoV-2, such as those targeted by antibodies, the EK1 peptide and other peptides reported to bind to the RBD, to aid in both structure-based vaccine and small molecule antiviral design.
Specifically, we will leverage our combined expertise in x-ray crystallography (Wilson), electron microscopy (Ward), and small-molecule discovery and medicinal chemistry (Wolan) to functionally characterize neutralization epitopes and antibody binding motifs and apply this information into high-throughput assays to aid in vaccine design, applications and use of therapeutic antibodies, and for discovery of specific high affinity small molecules to the S protein of SARS-CoV-2, as well as other coronaviruses, including SARS and MERS. We anticipate that
our structural characterization of novel Abs isolated from B cells of convalescent patients will provide critical information on surface hot spots, which can be targeted by vaccines and small molecules. As such, common features employed by antibodies for epitope recognition will inform on the tailored design of compounds as lead candidates for COVID-19 antivirals. Importantly, we will subject our small molecules to biologically relevant pseudovirus plaque assays and cell-based infection models, as well as human microsomal stability assays to generate a compendium of small molecules to move forward into translational studies.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Acute Nasopharyngitis><Affinity><Animal Model><Animal Models and Related Studies><Antibodies><Antigenic Determinants><Antiviral Agents><Antiviral Drugs><Antivirals><Assay><Aves><Avian><Awareness><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Bioassay><Biologic Assays><Biological><Biological Assay><Birds><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 anti-viral><COVID-19 antiviral><COVID-19 infected patient><COVID-19 patient><COVID-19 positive patient><COVID-19 virus><COVID19><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><CV19><Cell Body><Cells><Cessation of life><China><Cities><CoV-2><CoV2><Common Cold><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Cryo-electron Microscopy><Cryoelectron Microscopy><Death><Diagnosis><Disease Outbreaks><Electron Cryomicroscopy><Electron Microscopy><Epidemic><Epitope Mapping><Epitopes><External Domain><Extracellular Domain><Goals><HCoV><High Throughput Assay><Hot Spot><Human><Infection><MERS><MERS corona virus><MERS coronavirus><MERS coronavirus disease><MERS virus><MERS-CoV><MERS-CoV disease><Mainland China><Mammalia><Mammals><Medicinal Chemistry><Membrane Fusion><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome coronavirus disease><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome-CoV><Modeling><Modern Man><Molecular Interaction><Negative Staining><Outbreaks><Patients><Peptides><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Plaque Assay><Pneumonia><Proteins><RNA Viruses><Receptor Protein><Reporting><Respiratory Tract Diseases><SARS><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 anti-viral><SARS-CoV-2 antiviral><SARS-CoV-2 infected patient><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV2><SARS-CoV2 anti-viral><SARS-CoV2 antiviral><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><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><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><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 related corona virus 2><Severities><Single Crystal Diffraction><Structure><Surface><Testing><Therapeutic><Therapeutic Uses><Therapeutic antibodies><Upper respiratory tract><Vaccine Design><Vaccines><World Health Organization><Wuhan coronavirus><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-viral agents><anti-viral drugs><anti-virals><base><beta CoV><beta coronavirus><betaCoV><betacoronavirus><combat><corona virus><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 anti-viral><coronavirus disease 2019 antiviral><coronavirus disease 2019 infected patient><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus patient><cryo-EM><cryoEM><design><designing><develop a vaccine><development of a vaccine><hCoV19><high throughput screening><human CoV><human corona virus><human coronavirus><lead candidate><model of animal><model organism><mortality><nCoV2><novel><pandemic><pandemic disease><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><receptor><receptor binding><receptor bound><severe acute respiratory syndrome coronavirus 2 anti-viral><severe acute respiratory syndrome coronavirus 2 antiviral><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome-CoV><small molecule><stem><translational study><vaccine development><vaccine formulation><ward><β CoV><β coronavirus><βCoV>