# Covid-19: Fast-tracking treatment by exploiting the steroid hormone receptor/TMPRSS2 axis

> **NIH VA I01** · MIAMI VA HEALTH CARE SYSTEM · 2021 · —

## Abstract

COVID-19 poses a tremendous health threat, particularly to individuals overrepresented in the US
Veteran community. COVID-19 mortality is greater in men than in women; while this disparity is at least
partially due to factors such as higher rates of smoking, a hormonal link is likely and can be rapidly tested
therapeutically by repurposing existing drugs. The viral etiologic agent of COVID-19, SARS-CoV-2 (CoV-2),
attaches to human airway epithelium via the viral spike (S) protein, which binds to angiotensin-converting
enzyme 2 (ACE2) on the host cell surface. Viral entry requires S protein cleavage by the serine protease
TMPRSS2, which is a known transcriptional target of the androgen receptor (AR). Lung epithelial cells (a target
of CoV-2 infection) express transcriptionally active AR. We hypothesize that AR up-regulates TMPRSS2 in
lung epithelial cells and thereby promotes viral entry and infectivity. We propose that FDA-approved
AR antagonists will decrease CoV-2 entry and spread and can be rapidly repurposed for COVID-19. IL-6
is the major cytokine released in moderate and severe COVID-19 cases and both published and our
preliminary data show that IL-6 enhances AR transcriptional activity. We will therefore also examine the
contribution of interleukin 6 (IL-6) to AR regulation of TMPRRS2. To facilitate these studies in a robust manner,
we propose to isolate the SARS-CoV-2 entry mechanism through the use of luciferase-expressing
pseudovirions that harbor the SARS-CoV-2 S protein. Such a reporter system has high reproducibility,
versatility and dynamic range, allowing for the rapid, accurate and specific assessment of a large range of viral
entry regulators into primary human lung epithelial cells and lung adenocarcinoma cell lines under BSL2+
conditions. We will test whether AR inhibition reduces TMPRSS2 and the requisite S protein processing
thereby decreasing CoV-2 entry into host lung epithelial cells. Subsequently, we will confirm results on a
subset of promising compounds using live SARS-Cov-2 in an approved BSL3 facility. Safe and effective AR
antagonists are FDA approved for prostate cancer and this study will provide rationale to repurpose these
drugs for use in clinical trials for COVID-19.
 The glucocorticoid receptor (GR) shares a common DNA response element consensus sequence with
AR. Furthermore, GR upregulation of TMPRSS2 has been shown in advanced prostate cancer. Therefore, in
parallel, we will examine whether TMPRSS2 is regulated by glucocorticoids (cortisol) and blocked by a GR
antagonist in models of human lung epithelia. Patients taking corticosteroids (including the elderly and
individuals with diabetes, hypertension and chronic inflammatory disease) are at the highest risk of death from
COVID-19. The World Health Organization has provided interim guidance to avoid glucocorticoids in COVID-
19 patients with severe acute respiratory distress syndrome. Therefore, understanding GR regulation of
TMPRSS2 is also essential to re...

## Key facts

- **NIH application ID:** 10153099
- **Project number:** 1I01BX005466-01
- **Recipient organization:** MIAMI VA HEALTH CARE SYSTEM
- **Principal Investigator:** Kerry L Burnstein
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153099

## Citation

> US National Institutes of Health, RePORTER application 10153099, Covid-19: Fast-tracking treatment by exploiting the steroid hormone receptor/TMPRSS2 axis (1I01BX005466-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10153099. Licensed CC0.

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