Developing Lectins as Inhibitors of Coronavirus Spike Proteins - Project Summary/Abstract
In late 2019, the SARS-CoV2 virus emerged as a global pandemic, causing the severe respiratory disease
COVID-19 and resulting in millions of deaths worldwide. As a coronavirus, SARS-CoV2 host interactions are
dictated through the Spike proteins that encompass the virion. The Spike protein of SARS-CoV2, is a highly
glycosylated trimer that interacts with the ACE2 receptor on host cells via the receptor binding domain (RBD)
to facilitate viral entry. As a key player in viral infection, the Spike trimer, and the RBD, have become the target
for a majority of approved therapeutics and vaccines used to treat or prevent SARS-CoV2. In this proposal, the
PI uses a novel antiviral lectin, BOA, which he has demonstrated that BOA binds glycans on the spike protein,
and inhibits SARS-CoV2 viral entry. To understand how BOA inhibits viral entry, during the K99 phase of the
award, the PI will determine the mechanism by which BOA inhibits in SARS-CoV2 viral infection using a
combination of viral inhibition assays, biophysical assays, and electron microscopy. Subsequently the PI will
test the ability of BOA to inhibit emerging SARS-CoV2 variants of concern that have accumulated mutations to
various regions of the spike protein that facilitate immune escape. Expanding upon these findings during the
independent R00 phase of this award, the PI will use skills developed during the K99 phase to establish his
own independent research group, where they will test the ability of the BOA lectin to inhibit viral entry of Beta-
Coronaviruses known to infect humans. Successful completion of these aims could provide a bona fide broad
spectrum coronavirus inhibitor to be further developed as a therapeutic or diagnostic for the next coronavirus
that emerges. The proposed research, will provide the PI with new and exciting training in virology as well as
electron microscopy which he intends to pass on to his future trainees. The proposed work will be completed at
The University of Pittsburgh, where the Department of Structural Biology and Center for Vaccine Research will
provide unmatched access to resources, instrumentation, and experts in the field. The PI has assembled an
exciting mentorship team of virologists and biophysicists who he will meet with monthly to receive advice,
discuss results, designed new experiments, and prepare for transitioning into an independent career. To aide
in his career development, the university offers numerous workshops to develop skills such as grant writing
and mentorship. The PI will also attend conferences to give presentations and hone his science
communications skills. In Summary, the proposed training and career development plans will prepare the PI to
lead his own independent research group and become a leader in his field.
