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Principal Investigator: ELIZABETH ANN FITZPATRICK
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $645,603
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
COVID-19 was first identified in December 2019 in Wuhan, Hubei province, China, resulting in the ongoing 2019-
2020 pandemic. COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-
2). Common symptoms of the disease include fever, dry cough, shortness of breath, diarrhea, and loss of smell.
Complications may include pneumonia, viral sepsis, and acute respiratory distress syndrome. As of today, other
than remdesivir, there is no approved small molecule drug for the treatment of COVID-19 and the discovery of
an effective vaccine remains uncertain. Our long-term goal is to develop antiviral drugs for the treatment of
COVID-19 and human coronavirus infections in general. Our central hypothesis is that inhibition of SARS-CoV-
2 polyprotein cleavage results in the prevention and early treatment of COVID-19 before it progresses to its more
severe form. We will identify nanomolar inhibitors of the CoV 3C-like protease (3CLpro) suitable to be developed
as antiviral agents for the treatment of COVID-19 and other coronavirus infections. The proposal targets the
3CLpro, a key enzyme for SARS-CoV-2 polyprotein cleavage and viral replication. Our overall premise is that
small molecule inhibitors targeting this essential viral enzyme will inhibit replication, and therefore have the
potential to be of both preventive and therapeutic value. Thus, our primary objective is to design and develop
structure-based small-molecule inhibitors targeting coronavirus 3CLpro using our established and proven drug
discovery expertise. Guided by strong preliminary data, the inhibition of polyprotein cleavage hypothesis will be
tested by pursuing three specific aims: Aim 1) To inhibit SARS-CoV-2 polyprotein cleavage by developing
covalent peptidic inhibitors of 3CLpro (nsp5).; Aim 2) To inhibit SARS-CoV-2 polyprotein cleavage by developing
noncovalent nonpeptidic inhibitors of 3CLpro (nsp5).; and Aim 3) To determine the efficacy of covalent and
noncovalent SARS-CoV-2 3CLpro inhibitors in a golden hamster model. Under the first aim, lead compound
3150 and its analogs will be tested in viral and enzyme assays for inhibitory activity of SARS-CoV-2 3CLpro. An
aqueous soluble form of 3150 will be evaluated in the animal model. Structure-based drug design approaches
will be employed to optimize 3150 for binding to the crystal structure of SARS-CoV-2 3CLpro. Under aim 2,
Structure-based virtual screening and hybrid ligand screening approaches along with medicinal chemistry will
be used to prepare and evaluate noncovalent nonpeptidic inhibitors of 3CLpro. Under the third aim, top-ranked
SARS-CoV-2 3CLpro covalent and noncovalent inhibitors will be tested for pharmacokinetics and efficacy in a
golden hamster COVID-19 model. The ultimate goal of the proposed studies is to advance an anti-COVID-19
drug candidate to the stage of filing an investigational new drug (IND) application. Overall, the results of this
project will have a significant positive impact because they lay the groundwork for the clinical development of
COVID-19 antiviral therapy and the potential to combine a potent and selective protease inhibitor with a
nucleoside analog (e.g., remdesivir) and if needed anti-inflammatory drugs (e.g., dexamethasone or baricitinib).
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