Document text
Principal Investigator: Xi Chen
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2020
Award: $195,234
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Exploring the biology of O-acetyl sialic acids using stable synthetic mimics
This supplement request explores the possibility that sialoglycans may be co-receptors for SARS and COVID-
19 virus spike (S) proteins, as is the case with MERS and other Coronaviruses (CoVs). Numerous viruses
recognize host cell surface glycans that terminate in sialic acids (Sias), a family of 9-carbon-backbone
monosaccharides present at very high densities on all vertebrate cell surfaces, and on most secreted proteins–
–particularly mucins that line and protect mucosal surfaces like the airways. Viral recognition of host sialoglycans
is affected by Sia type, linkage to, and the structure of underlying glycans. Much of this natural diversity of Sias
in viral infection remains underexplored. While many respiratory disease-causing viruses target Sias, Sia
recognition is not currently reported in SARS-CoV-2, the COVID-19 pandemic virus. This stands in contrast to
the extensive literature on Coronaviruses and Sia receptors and is likely because a definitive human protein
receptor (ACE2) for the virus S protein has been identified. A similar situation existed for the earlier MERS-CoV
which had a well-defined receptor (DPP4) but was later found to also bind Sias via a different binding site. Given
the very high Sia density in vivo, and the fact that Sias are the first contact of a virus on a mucosal surface, Sia
diversity is likely to play important roles during natural infections. We hypothesize that airway Sias are also
recognized by S proteins of SARS-CoV-1 and SARS-CoV-2. This supplement is based on strong foundations
built by decades of studies of Sia diversity by the collaborating labs, including the parent project which addresses
instability of Sia O-acetyl modifications by synthesizing sialosides with corresponding N-acetyl analogs. The
urgent need for more careful exploration of Sia-binding functions of SARS and MERS will utilize a unique
sialoglycan microarray built up over years of collaboration between the labs. Additional diversity of human
sialosides such as those with 9-O-lactyl Sia that have heretofore not been studied, but could be critical, will also
be explored. We propose sialoglycan microarray studies of recombinant soluble external domains of S proteins
of MERS-CoV, SARS-CoV-1 and SARS-CoV-2 in comparison with human CoVs causing milder diseases, to
detect Sia-dependent binding that has been missed so far. We will synthesize sialosides containing naturally
occurring 9-O-lactyl-Sia and more stable 9-N-lactyl analogs and integrate these with the microarray and binding
studies. Computational studies, including molecular dynamics simulation of binding free energies, will
complement the array studies by predicting Sia variants that might bind, and modelling binding seen in array
studies. These studies will generate new knowledge that may help to better understand viral infection,
pathogenesis, and transmission from animals to humans and among humans. Additional viral epitopes critical
for binding neutralization may be identified that could suggest novel preventative and/or therapeutic approaches
to COVID-19. This project is therefore well suited to the urgency of the current pandemic situation. Information
learned can also be applied toward the prediction and prevention of future epidemics and pandemics.
Terms: <2019 novel coronavirus><2019-nCoV><Acetate Esterase><Acetic-ester acetylhydrolase><Acetylase><Acetylation><Acetylesterase><Acid Esterase><Acute Nasopharyngitis><Acylneuraminyl hydrolase><Address><Affect><Affinity><Animals><Antigenic Determinants><Aves><Avian><Avidity><Binding><Binding Determinants><Binding Proteins><Binding Sites><Biology><Birds><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><Carbon><Cell Communication><Cell Interaction><Cell surface><Cell-to-Cell Interaction><Charge><Collaborations><Combining Site><Common Cold><Complement><Complement Proteins><Coronaviridae><Coronavirus><Detection><Dipeptidyl Aminopeptidases><Dipeptidyl Peptidases><Dipeptidylpeptide Hydrolases><Disease><Disorder><Enzyme Gene><Enzymes><Epidemic><Epitopes><Esterase-17><External Domain><Extracellular Domain><Family><Foundations><Free Energy><Future><GcNeu><Glycans><Goals><HCoV><Hemagglutinin><Human><Hydroxyl><Hydroxyl Radical><In Vitro><Infection><Influenza A><Influenza A virus><Influenza B><Influenza B Virus><Influenza C><Influenza C Virus><Influenza Viruses Type A><Influenza Viruses Type B><Influenza Viruses Type C><Influenzavirus A><Influenzavirus C><Knowledge><Lactams><Lactone Compound><Lactones><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Literature><Lung diseases><MERS><MERS corona virus><MERS coronavirus><MERS coronavirus disease><MERS virus><MERS-CoV><MERS-CoV disease><Mediating><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><Modification><Molecular Dynamics Simulation><Molecular Interaction><Monosaccharides><Mucins><Mucosa><Mucosal Tissue><Mucous Membrane><Mucus Glycoprotein><N-Acetylneuraminic Acid><N-Acetylneuraminic Acids><N-Acylneuraminate Glycohydrolases><N-glycoloylneuraminic acid><N-glycolylneuraminic acid><NGNA><Nature><Neuraminidase><O element><O2 element><Oligosaccharide Sialidase><Orthomyxovirus Type A><Orthomyxoviruses Type B><Orthomyxoviruses Type C><Oxygen><Pathogenesis><Physiologic><Physiological><Play><Polysaccharides><Population><Prevention><Protein Binding><Proteins><PubMed><Pulmonary Diseases><Pulmonary Disorder><Reactive Site><Receptor Protein><Recombinants><Reporting><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Role><SARS><SARS Virus><SARS corona virus><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Severe Acute Respiratory Syndrome><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 coronavirus 2><Sialic Acids><Sialidase><Spanish flu><Spanish influenza><Spinal Column><Spine><Structure><Sulfate><Surface><Surface Properties><Testing><Therapeutic><Transmission><Type A Influenza><Variant><Variation><Vertebral column><Viral><Viral Diseases><Virus><Virus Diseases><Wuhan coronavirus><amino group><analog><backbone><base><bound protein><computational studies><computer studies><corona virus><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 epidemic><coronavirus disease 2019 pandemic><density><disease of the lung><disorder of the lung><exo alpha sialidase><experiment><experimental research><experimental study><flu><hemagglutinin esterase><human CoV><human corona virus><human coronavirus><human disease><in vivo><lung disorder><molecular dynamics><novel><pandemic><pandemic disease><pandemic flu><pandemic influenza><pandemic strain of influenza><parent project><pathogen><preference><protein protein interaction><receptor><severe acute respiratory syndrome-CoV><social role><sugar><transmission process><viral infection><virus infection><virus-induced disease>