The inhaled steroid ciclesonide blocks SARS-CoV-2 RNA replication by targeting the viral replication-transcription complex in cultured cells

Here, we screened steroid compounds to obtain a drug expected to block host inflammatory responses and MERS-CoV replication Ciclesonide, an inhaled corticosteroid, suppressed replication of MERS-CoV and other coronaviruses, including SARS-CoV-2, the cause of COVID-19, in cultured cells The effective concentration (EC(90)) of ciclesonide for SARS-CoV-2 in differentiated human bronchial tracheal epithelial cells was 0 55 μM Eight consecutive passages of 43 SARS-CoV-2 isolates in the presence of ciclesonide generated 15 resistant mutants harboring single amino acid substitutions in non-structural protein 3 (nsp3) or nsp4 Of note, ciclesonide suppressed replication of all these mutants by 90% or more, suggesting that these mutants cannot completely overcome ciclesonide blockade Under the microscope, the viral RNA replication-transcription complex in cells, which is thought to be detectable using antibodies specific for nsp3 and double stranded RNA, was observed to fall in the presence of ciclesonide in a concentration-dependent manner These observations indicate that the suppressive effect of ciclesonide on viral replication is specific to coronaviruses, highlighting it as a candidate drug for the treatment of COVID-19 patients IMPORTANCE The outbreak of SARS-CoV-2, the cause of COVID-19, is ongoing New and effective antiviral agents that combat the disease are needed urgently Here, we found that an inhaled corticosteroid, ciclesonide, suppresses replication of coronaviruses, including beta-coronaviruses (MHV-2, MERS-CoV, SARS-CoV, and SARS-CoV-2) and an alpha-coronavirus (HCoV-229E), in cultured cells Ciclesonide is safe;indeed, it can be administered to infants at high concentrations Thus, ciclesonide is expected to be a broad-spectrum antiviral drug that is effective against many members of the coronavirus family It could be prescribed for treatment of MERS and COVID-19