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Principal Investigator: Stefan G Sarafianos
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $678,703
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) cause severe diseases in humans (COVID-
19) that presents a major threat for global public health. Since it was first reported in 12/2019, COVID-19 has
become a pandemic that continues to spread, with >246 million confirmed cases and >5 million deaths as of
11/02/2021. In addition to the human tragedy, the magnitude of the pandemic-driven implosion of global
economies is enormous. Although vaccines are now available, their efficacy appears to be reduced with
spreading viral strains. Remdesivir is the only approved antiviral targeting SARS-CoV-2, but it has little effect on
COVID-19 mortality. Therefore, it is critical to identify and develop additional antivirals to combat viral infection.
The following strong preliminary data enable targeting of SARS-CoV-2: 1) Construction of an extensive
collection of SARS-CoV-2 replicon systems that enable cutting-edge, rapid, and economical high-throughput
screening. 2) Preparation of cell lines that stably express SARS-CoV-2 replicon. 3) Preliminary screening of
chemical libraries led to the discovery of a novel SARS-CoV-2 antiviral, which has already been improved with
one round of optimization through medicinal chemistry efforts. 4) Multiplex visualization of single-genomic or
subgenomic (+) or (-) SARS-CoV-2 RNA and simultaneously viral and/or host proteins in individual infected cells.
5) Cutting-edge rapid high-throughput infectious virus BSL3 assays that enable kinetic, mechanistic, drug
resistance studies. 6) In-house cloning expression and purification of 10 SARS-CoV-2 non-structural proteins
(nsps). 7) Biochemical and biophysical assays to measure the enzymatic activities of several SARS-CoV and
SARS-CoV-2 nsp proteins and to measure compound binding to nsps.
We hypothesize that our recently developed replicon systems can be used for the discovery of anti-SARS-
CoV-2 hits, which upon hit-to-lead optimization can become COVID-19 drug candidates. To address this
hypothesis, we propose the following specific aims:
1. Use of SARS-CoV-2 replicon plasmid systems and SARS-CoV-2 replicon-expressing cell lines to screen
chemical libraries for antiviral hits.
2. Inhibition and resistance studies with prioritized inhibitors.
3. Hit-to-lead optimization
These studies will lead to antivirals with strong potency and pharmacokinetic profiles, setting the stage for
development of SARS-CoV-2 antivirals and combination therapies.
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