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

Abstract

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 (EC90) of ciclesonide for SARS-CoV-2 in differentiated human bronchial tracheal epithelial cells was 0.55 μM. Ciclesonide inhibited formation of double membrane vesicles, which anchor the viral replication-transcription complex in cells. 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 still suppressed replication of all these mutants by 90% or more, suggesting that these mutants cannot completely overcome ciclesonide blockade. 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.

Asthma did not increase in‐hospital COVID‐19‐related mortality in a tertiary UK hospital

“…However, COVID-19 infection, age, male gender and HDU/ ICU admission conferred significantly increased risk for in-hospital death.explained by the fact that our SA clinics at UHS were switched to remote consultations and offered intensified virtual patient access during the height of the pandemic. Furthermore, 55% of our SA patients formally shielded according to government mandate Additionally, our SA patients were on high dose inhaled corticosteroids, namely ciclesonide which has been shown to inhibit SARS-CoV-2 replication in vitro and attracted interest as a potential COVID-19 therapy 8. Our findings for SA mortality were consistent with recently published findings from the UK Severe Asthma Registry.…”

Immunomodulation as a Potent COVID-19 Pharmacotherapy: Past, Present and Future

“…In COVID-19, inhaled corticosteroid ciclesonide inhibited SARS-CoV-2 ribonucleic acid (RNA) replication by targeting viral replication-transcription complex. 20 Despite the failure of corticosteroids to show significant benefits and their association with delayed viral clearance in previous coronavirus (SARS-CoV-1 and MERS-CoV) diseases, studies investigating the effects of corticosteroids in COVID-19 showed several promising results. 21 For example, methylprednisolone lowered COVID-19-associated mortality in patients with acute respiratory distress syndrome and reduced the duration of supplemental oxygen in COVID-19 patients.…”

Drug repurposing approach to combating coronavirus: Potential drugs and drug targets

“…Ciclesonide ( 90 ) is an inhaled corticosteroid used to treat asthma and allergic rhinitis 354 . It inhibits SARS‐CoV‐2 replication (EC 50 = 4.33 µM), and mutants in nsp3 and nsp4 of SARS‐CoV‐2 showed resistance against ciclesonide 70,355 . Cases were also reported that ciclesonide inhalation treatment was associated with clinical improvement in three COVID‐19 patients 356 .…”