Effect of antiandrogens on the tropism of seasonal human coronaviruses

Human coronaviruses (HCoVs) are positive-sense, single-stranded RNA viruses. The HCoVs: OC43 and 229E, HKU1 and NL63 cause 10-30% of common colds with mild respiratory symptoms and more severe disease in immunocompromised patients or the elderly. The emergence and severity of COVID-19 has heightened the need to study the seasonal HCoVs (sHCoVs) to comprehend the pathogenicity mechanisms of coronaviruses. Cellular entry of SARS-CoV-2 is largely dependent on the viral spike (S) protein which binds to the cell surface receptor Angiotensin-Converting Enzyme 2 (ACE2) and is proteolytically cleaved by Transmembrane Serine Protease 2 (TMPRSS2) into two subunits. Studies have shown that TMPRSS2 can also facilitate entry of the HCoV-229E and -NL63. Hence, TMPRSS2 is an attractive therapeutic target as knockout of this protein causes no overly detrimental phenotype unlike ACE2 which is critical to regulating processes such as blood pressure. The sequence alignment analysis shows that the TMPRSS2 cleavage site is well conserved across all sHCoVs therefore TMPRSS2 can potentially cleave the S protein of the sHCoVs. This work further demonstrates that TMPRSS2 at least partially facilitates cell entry of HCoV-229E and NL63. TMPRSS2 targets the androgen receptor and drugs antiandrogens, e.g. enzalutamide that target this transcription factor have been have been found to reduce TMPRSS2 expression and prevent viral entry. Hence, it is hypothesised that similar to SARS-CoV-2, antiandrogens can be used against sHCoVs. Importantly enzalutamide successfully reduced entry of HCoV: 229E and NL63 pseudotype virus, which are enveloped viral particles comprised of a viral capsid surrounded by a cell derived membrane bearing the desired viral envelope protein. Therefore highlighting TMPRSS2 as a potential therapeutic target and antiandrogens as a potential therapy for sHCoVs. In addition, using an androgen response element driven reporter, HCoV-229E infection was found to induce androgen receptor activity and differential expression of androgen regulated genes, indicating a crosstalk between infection and AR signalling