Document text
Principal Investigator: Houjian Cai
Organization: UNIVERSITY OF GEORGIA
Fiscal Year: 2021
Award: $226,500
Funding agency: National Institute of Allergy and Infectious Diseases
Summary/Abstract
SARS-CoV-2 has infected over 51 million and is responsible for the death of over 1.27 million people
globally. Interventions to address both prevention and treatment are urgently needed. Infection of SARS-CoV-
2 requires the host serine protease TMPRSS2 to activate the virus spike protein for interaction with the host
ACE2 receptor and entry into host cells. TMPRSS2 levels are significantly regulated by androgen receptor
signaling in prostate cancer cells, but unknown in respiratory epithelial cells. Numerous inhibitors have been
developed to target AR signaling. The toxicity, effective dosage, and side effects of these inhibitors have been
well-documented. We hypothesize that reducing TMPRSS2 levels by blocking AR signaling will block activation
of the spike protein of SARS-CoV-2 in respiratory epithelial cells, thereby preventing its entry into host cells in
the respiratory system. Our preliminary data indicate that genetic and pharmacological inhibition of AR signaling
suppresses TMPRSS2 levels, and an AR signaling inhibitor significantly inhibits pseudotype virus infection in
prostate cancer cells. In this proposal, we will examine whether AR signaling inhibitors will suppress TMPRSS2
levels in respiratory epithelial cells leading to inhibition of TMPRSS2-catalyzed proteolysis of the SARS-CoV-2
spike protein in vitro, subsequently mitigating its infection efficiency. Next, we will investigate if targeting
TMPRSS2 levels will inhibit SARS-CoV-2 infection through the respiratory route in vivo. In particular, we will
examine the SARS-CoV-2 infection efficiency in mice deficient in TMPRSS2 or androgen production. We will
investigate if AR signaling inhibitors will reduce TMPRSS2 levels in vivo, and mitigate SARS-CoV-2 infection in
respiratory system. The goal of this proposal is to examine TMPRSS2 as a target and identify an effective drug
from currently known AR signaling inhibitors to inhibit SARS-CoV-2 infection. Although SARS-CoV-2 vaccine is
under development and might be effective, this study will provide a therapeutic treatment option of suppressing
SARS-CoV-2 infection in the host, thus reducing the severity of COVID-19 symptoms and ultimately preventing
deaths from COVID-19.
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