Hormone Drugs May Disarm Coronavirus Spike Protein and Stop COVID-19 Disease Progression

Hormone drugs can turn off COVID-19 spike, Penn study suggests. Credit: Getty Images

A new study from Penn Medicine shows how antiandrogen drugs disrupt key receptors required for viral invasion of cells.

Hormone drugs that lower androgen levels may help disarm the coronavirus spike protein used to infect cells and halt the progression of severe COVID-19 disease, new preclinical study from Abramson Cancer Center researchers suggests at the University of Pennsylvania and published online in Cell Press on iScience.

Researchers show how two receptors – known as ACE2 and TMPRSS2 – are regulated by the androgen hormone and used by SARS-CoV-2 to access host cells. Blocking the receptors with the clinically proven inhibitor Camostat and other antiandrogen therapies prevented viral entry and replication, they also showed in laboratory studies.

The findings provide greater insight into the virus’s molecular mechanisms, but also support the use of antiandrogen therapies to treat COVID-19 infections, which are currently under investigation in clinical trials and have shown promising results. They also support data showing increased mortality and disease severity in men compared to women, who have much lower androgen levels.

“We provide the first evidence that not only TMPRSS2, which is known to be regulated by androgen, but ACE2 can also be directly regulated by this hormone,” said senior author Irfan A. Asangani, PhD, an assistant professor of cancer biology. the Perelman School of Medicine at the University of Pennsylvania. “We also show that the SARS-CoV-2 peak relies on these two receptors to pierce and enter cells, and that they can be blocked with existing drugs. That’s important because if you stop viral access, you reduce viral load and disease progression. “

Camostat is a drug approved for use in Japan to treat pancreatitis that inhibits TMPRSS2. Other anti-androgen therapies, including androgen deprivation therapy used to treat prostate cancer, have similar functions.

Driven by the disparity in COVID-19 rates between men and women, the cancer researchers sought to better understand the role of androgen and its receptors in infections that have long been known to cause prostate cancer.

The researchers experimented with a pseudotype SARS-CoV-2, which carries the virus’s spike proteins, but not the genome.

In mice with significantly reduced androgen levels and cells treated with antiandrogen treatments, the researchers found little to no expression of TMPRSS2 and ACE2, suggesting that both are regulated by the hormone. They also saw how inhibiting TMPRSS2 with Camostat blocked the priming of the peak for entry into cells. That drug, like enzalutamide, an anti-androgen therapy used to treat prostate cancer, also blocked the virus’s access to lung and prostate cells. By combining these therapies, they found that virus entry into cells was significantly reduced.

“Together, our data provides a strong rationale for clinical evaluations of TMPRSS2 inhibitors, androgen deprivation therapy / androgen receptor antagonists alone or in combination with antivirals as early as clinically possible to prevent COVID-19 progression,” the authors wrote.

In March, researchers from Brazil reported preliminary results from 600 hospitalized patients in a clinical trial investigating proxalutamide, a new antiandrogen therapy, for the treatment of COVID-19. The drug reduced the risk of death by 92 percent and shortened median hospital admission by nine days from standard care, the researchers reported.

Next, Asangani and colleagues will work with Susan R. Weiss, PhD, a professor of microbiology and co-director of the Penn Center for Research on Coronaviruses and Other Emerging Pathogens, to further investigate the findings using live SARS-CoV-2, as well as the ability of antiandrogen therapies to block different variants of the virus that keep emerging and are often differentiated by their peak proteins.

Reference: “Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19” by Qu Deng, Reyaz ur Rasool, Ronnie M. Russell, Ramakrishnan Natesan and Irfan A. Asangani, Mar 1, 2021, iScience.
DOI: 10.1016 / j.isci.2021.102254

Penn co-authors on the study include Qu Deng, Reyaz ur Rasool, Ronnie M. Russell, and Ramakrishnan Natesan.