Therapeutic targeting of TMPRSS2 andACE2 as a potential strategy to combat COVID-19

ABSTRACT

The novel SARS-CoV-2 infection responsible for the COVID-19 pandemic is expected to have an adverse effect onthe progression of multiple cancers, including prostate cancer, due to the ensuing cytokine storm associatedoncogenic signaling. A better understanding of the host cell factors and their regulators will help identify potentialtherapies to block SARS-CoV-2 infection at an early stage and thereby prevent cancer progression. Host cellinfection by SARS-CoV-2 requires the binding of the viral spike S protein to ACE2 receptor and priming by theserine protease TMPRSS2-encoded by a well-known androgen response gene and highly expressed in patientsdiagnosed with prostate cancer. Epidemiologic data showing increased severity and mortality of SARS-CoV-2disease in men suggest a possible role for androgen in the transcriptional activation of ACE2 and TMPRSS2 in thelungs and other primary infection sites. Here, by performing in vivo castration in mice, RT-PCR, immunoblotting, Co-IP, and pseudovirus infection assays in multiple cell lines, we present evidence for the transcriptional regulation ofTMPRSS2 and ACE2 by androgen, their endogenous interaction, as well as a novel combination of drugs inblocking viral infection. In adult male mice, castration led to a significant loss in the expression of ACE2 andTMPRSS2 at the transcript and protein levels in the lung, heart, and small intestine. Intriguingly, castrated micedisplayed a substantial increase in ACE2 in the kidney, which could potentially be due to the low blood pressureresulting from androgen deprivation. Endogenous TMPRSS2 and ACE2 were found to be physically interacting, asobserved by reciprocal immunoprecipitation followed by immunoblotting. Importantly, along with full-length zymogenform, a prominent novel small isoform of TMPRSS2 was found to be associated with ACE2 in lung and prostatecells. In an overexpression system, camostat-a serine protease inhibitor specific to TMPRSS2-inhibited thecleavage of spike S, suggesting a direct role of this serine protease in priming the viral spike S protein, aprerequisite for an active infection. Furthermore, a combination of camostat, antiandrogen, and epigenetic drugs atsublethal concentrations blocked SARS-CoV-2 pseudovirus infection in multiple cell types. Together, our preclinicaldata provide a strong rationale for clinical evaluation of TMRPSS2 inhibitors, antiandrogens, and epigenetic drugcombinations along with antiviral drug remdesivir as early as clinically possible to prevent progression to pneumoniaand multiorgan failure as a result of hyperinflammatory responses in COVID-19 patients.