Apalutamide Prevents SARS-CoV-2 Infection in Lung Epithelial Cells and in Human Nasal Epithelial Cells

Abstract

In early 2020, the novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, and rapidly propagated worldwide causing a global health emergency. SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) protein for cell entry, followed by proteolytic cleavage of the Spike (S) protein by the transmembrane serine protease 2 (TMPRSS2), allowing fusion of the viral and cellular membranes. Interestingly, TMPRSS2 is a key regulator in prostate cancer (PCa) progression which is regulated by androgen receptor (AR) signaling. Our hypothesis is that the AR signaling may regulate the expression of TMPRSS2 in human respiratory cells and thus influence the membrane fusion entry pathway of SARS-CoV-2. We show here that TMPRSS2 and AR are expressed in Calu-3 lung cells. In this cell line, TMPRSS2 expression is regulated by androgens. Finally, pre-treatment with anti-androgen drugs such as apalutamide significantly reduced SARS-CoV-2 entry and infection in Calu-3 lung cells but also in primary human nasal epithelial cells. Altogether, these data provide strong evidence to support the use of apalutamide as a treatment option for the PCa population vulnerable to severe COVID-19.

Antiandrogens as Therapies for COVID-19: A Systematic Review

“…Subsequent in vivo studies later disproved these results and abiraterone has consequently not been employed as an anti-viral treatment [57][58][59]. The effect of apalutamide, an oral competitive signaling inhibitor of the ligand-binding domain of the androgen receptor, on SARS-CoV-2 infection has also been tested by in vitro studies with Calu-3 lung adenocarcinoma cells and primary human nasal epithelial cells, finding a reduction in SARS-CoV-2 entry [6]. Proxalutamide is a novel third-generation antiandrogen that is currently under investigation for PC treatment.…”

“…At the molecular level, there is an increasing body of evidence that COVID-19 infection follows specific pathways, and the identification of SARS-CoV-2 entry mechanisms into host cells established the basis for the investigation of new therapies [6].…”

“…At the molecular level, there is an increasing body of evidence that COVID-19 infection follows specific pathways, and the identification of SARS-CoV-2 entry mechanisms into host cells established the basis for the investigation of new therapies [6] 1.1. SARS-CoV-2 Structure SARS-CoV-2 is an enveloped viral particle containing a single-stranded positive sense RNA genome [7,8].…”

“…SARS-CoV-2 Structure SARS-CoV-2 is an enveloped viral particle containing a single-stranded positive sense RNA genome [7,8]. The virion comprises RNA associated with nucleoproteins (Ns and membrane (M), spike (S) and envelope (E) capsid proteins involved in mediating hos and viral membrane fusion [6] (Figure 1).…”