Inhibition of coronavirus release and mitigate COVID-19 pathogenesis

NIH Pandemic-Era Grants

Pandemic Era Grants

2021

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Principal Investigator: PETER D. SUN
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2021
Award: $158,373
Funding agency: National Institute of Allergy and Infectious Diseases

To characterize the SARS-CoV-2 spike protein interaction with lectin receptors, we have expressed recombinant SARS-CoV-2 spike prefusion trimer using 293F freestyle expression system.  Given the nanomolar high affinity of the spike protein binding to human ACE2, the entry receptor for SARS-CoV-2, and the physiological importance of ACE2 in balancing blood pressure, we investigated if this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity 3-10 fold when fluorogenic caspase-1 substrate and Bradykinin-analog peptides were used to characterize ACE2 activity.  In addition, the enhancement was mediated by ACE2 binding of RBD domain of SARS-CoV-2 spike. These results highlighted the altered activity of ACE2 during SARS-CoV-2 infection and would shed new lights on the pathogenesis of COVID-19 and its complications for better treatments. A manuscript describing this finding is under revision for publication in Journal of Biological Chemistry.
In addition, we begin to construct a pseudo-coronavirus with SARS-CoV-2 spike envelope.  We are in the process to express several lectin receptors either recombinantly or on cell surface.

Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acylneuraminyl hydrolase><Affect><Affinity><Antiviral Agents><Antiviral Drugs><Antivirals><Apoptosis-Related Cysteine Protease Caspase 1><Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg><Binding><Binding Proteins><Biochemistry><Biological Chemistry><Blood Pressure><Bradykinin><CASP-1><CASP1><CASP1 gene><COVID disease severity><COVID severity><COVID-19><COVID-19 S protein><COVID-19 disease severity><COVID-19 infection><COVID-19 pathogenesis><COVID-19 severity><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19><COVID19 S protein><COVID19 disease severity><COVID19 infection><COVID19 pathogenesis><COVID19 severity><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><CV-19><CV19><Caspase-1><Caspase-1 Gene><Cell surface><Clinical><CoV S protein><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><CoV-2><CoV2><Coronaviridae><Coronavirus><Coronavirus glycoprotein S><Coronavirus spike protein><Drug Targeting><Equilibrium><Fibrin><Glycans><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV env Protein gp120><HTLV-III gp120><Human><Human Immunodeficiency Viruses><ICE Protease><IL-1 beta Convertase><IL-1 beta-Converting Enzyme><IL-1BC><IL-1b Converting Enzyme><IL1B-Convertase><IL1BC><IL1BCE><Influenza Virus><Interleukin 1-B Converting Enzyme><Interleukin 1-Beta Convertase><Interleukin-1 Beta Converting Enzyme><Interleukin-1 Converting Enzyme><Journals><LAV-HTLV-III><Lectin Receptors><Ligand Binding Protein><Ligand Binding Protein Gene><Lymphadenopathy-Associated Virus><Magazine><Manuscripts><Mediating><Metabolic Glycosylation><Metallopeptidases><Metalloproteases><Metalloproteinases><Modern Man><Molecular Interaction><N-Acetylneuraminic Acids><N-Acylneuraminate Glycohydrolases><Neuraminidase><Oligosaccharide Sialidase><Oseltamivir><Pathology><Physiologic><Physiological><Polysaccharides><Process><Protein Binding><Proteins><Publications><Receptor Inhibition><Receptor Protein><Recombinants><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 disease severity><SARS-CoV-2 infection><SARS-CoV-2 inhibitor><SARS-CoV-2 severity><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Scientific Publication><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-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 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 inhibitor><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Sialic Acids><Sialidase><Site><System><Tamiflu><Therapeutic><Viral><Virus-HIV><Wuhan coronavirus><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-viral agents><anti-viral drugs><anti-virals><balance><balance function><block SARS-CoV-2><block severe acute respiratory syndrome coronavirus 2><bound protein><corona virus><corona virus disease 2019><coronavirus S protein><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 disease severity><coronavirus disease 2019 infection><coronavirus disease 2019 pathogenesis><coronavirus disease 2019 severity><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease severity><coronavirus spike glycoprotein><exo alpha sialidase><glycosylation><gp120><gp120 ENV Glycoprotein><gp120(HIV)><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><influenzavirus><inhibit SARS-CoV-2><inhibit severe acute respiratory syndrome coronavirus 2><kallidin 9><kallidin I><nCoV2><nano-molar><nanomolar><pandemic><pandemic disease><peptide analog><receptor><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 severity>