Hormone drugs that lower androgen levels may help disarm the spike coronavirus protein used to enter cells and stop the progression of COVID-19 disease, a study suggests new preclinical from researchers at the Abramson Cancer Center at the University of Pennsylvania and published online at IScience Cell Press.
Researchers show how two receptors – called ACE2 and TMPRSS2 – are regulated by the androgen hormone and used by SARS-CoV-2 to enter host cells. By blocking the receptors with the clinical inhibitor Camostat and other anti-androgen therapies that prevented viral entry and reproduction, they also showed up in laboratory studies.
The findings provide more insight into the molecular mechanisms of the virus but also support the use of anti-androgen therapies to treat COVID-19 infections, which are currently being studied in their clinical trials and gave promising results. They also support data showing greater mortality and severity of disease among men compared to women, who have much lower levels of androgen.
We present the first evidence that not only TMPRSS2, which is known to be regulated by androgen, but ACE2 can be directly regulated by this hormone. We also show that the SARS-CoV-2 spike is responsible for these two receptors entering and entering cells, and that they can be blocked by the drugs that are there. This is important because stopping viral entry will reduce the viral load and the progression of disease. “
Irfan A. Asangani, PhD, S.enior Author, A.ssistant Professor of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania
Camostat is a drug approved for use in Japan to treat pancreatitis that inhibits TMPRSS2. Other anti-androgen therapies, including androgen deficiency therapy used to treat prostate cancer, serve similar functions.
Led by the difference in COVID-19 levels between men and women, the cancer researchers sought to better understand the role of androgen and its receptors in diseases, which has long been known as a prostate cancer driver.
The researchers experimented with pseudotype SARS-CoV-2, which carries the virus’s spike proteins but not its genome.
In mice with severely reduced androgen levels and cells treated with anti-androgen therapies, the researchers found little to no explanation for TMPRSS2 and ACE2, suggesting that both some are regulated by the hormone. They also saw how the inhibition of TMPRSS2 by Camostat prevented a spike from entering cells. That drug, in addition to enzalutamide, an anti-androgen medication used to treat prostate cancer, also blocked the entry of the virus into lung and prostate cells. Combined with these therapies, they found, they significantly reduced virus entry into cells.
“Together, our data provide a robust rationale for clinical evaluations of TMPRSS2 antagonists, androgen-depleting antagonists / androgen receptor antagonists alone or in combination with antiviral drugs as early as clinically possible. to prevent the progression of COVID-19, “the authors wrote.
In March, researchers from Brazil reported the initial results of 600 hospitalized patients in a clinical trial examining proxalutamide, a new androgen antagonist, for the treatment of COVID-19. The drug reduced the risk of death by 92 percent and shortened the hospital stay by nine days compared to the standard of care, the researchers said.
Next, Asangani and his colleagues will partner with Susan R. Weiss, PhD, professor of Microbiology and co-director of the Penn Center for Research on Emerging Coronaviruses and Pathogens, to further study the findings using live SARS-CoV-2, as well as the ability of anti-androgen therapies to prevent various strains of the virus, which are still present and often they differ by their spike proteins.
University of Pennsylvania School of Medicine
Deng, Q., et al. (2021) Focusing on androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19. iScience. doi.org/10.1016/j.isci.2021.102254.