Inhibition of coronavirus release and mitigate COVID-19 pathogenesis

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Principal Investigator: PETER D. SUN
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2020
Award: $143,327
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.

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