Cyclosporin A: A Repurposable Drug in the Treatment of COVID-19?

Abstract

Coronavirus disease 2019 (COVID-19) is now at the forefront of major health challenge faced globally, creating an urgent need for safe and efficient therapeutic strategies. Given the high attrition rates, high costs, and quite slow development of drug discovery, repurposing of known FDA-approved molecules is increasingly becoming an attractive issue in order to quickly find molecules capable of preventing and/or curing COVID-19 patients. Cyclosporin A (CsA), a common anti-rejection drug widely used in transplantation, has recently been shown to exhibit substantial anti-SARS-CoV-2 antiviral activity and anti-COVID-19 effect. Here, we review the molecular mechanisms of action of CsA in order to highlight why this molecule seems to be an interesting candidate for the therapeutic management of COVID-19 patients. We conclude that CsA could have at least three major targets in COVID-19 patients: (i) an anti-inflammatory effect reducing the production of proinflammatory cytokines, (ii) an antiviral effect preventing the formation of the viral RNA synthesis complex, and (iii) an effect on tissue damage and thrombosis by acting against the deleterious action of angiotensin II. Several preliminary CsA clinical trials performed on COVID-19 patients report lower incidence of death and suggest that this strategy should be investigated further in order to assess in which context the benefit/risk ratio of repurposing CsA as first-line therapy in COVID-19 is the most favorable.

A Review on Measures to Rejuvenate Immune System: Natural Mode of Protection Against Coronavirus Infection

“…Cyclosporine A is used to cure inflammatory diseases. It has played a significant role in viral infection, either promoting or inhibiting their replication ( 213 ). Additionally, cyclosporine A prevents replication of all genera of coronavirus, including SARS-CoVs and avian infectious bronchitis virus ( 214 ).…”

Solid organ transplantations and COVID-19 disease

“…Calcineurin inhibitors attach to intracellular cyclophilin, which is an immunophilin, and this calcineurin inhibitor-immunophilin complex inhibits nuclear factor of activated T-cells (NFAT). As a result of NFAT inhibition, cytokine transcription and T-cell activation are blocked[ 32 ]. The cyclosporine level needed to prevent virus replication surpasses by far the serum levels that characteristically are well below 200 ng/mL[ 32 ].…”

“…As a result of NFAT inhibition, cytokine transcription and T-cell activation are blocked[ 32 ]. The cyclosporine level needed to prevent virus replication surpasses by far the serum levels that characteristically are well below 200 ng/mL[ 32 ]. This indicates that the dose utilized to manage most patients with cyclosporine is too low to successfully eliminate the virus.…”

“…This indicates that the dose utilized to manage most patients with cyclosporine is too low to successfully eliminate the virus. One of the issues is to reach adequate tissue level, as the key virus load is in the respiratory tract and lungs rather than in serum and the cyclosporine concentration in the lungs is lesser than in serum[ 32 ]. Additionally, the necessary dosage for vigorously treating severe COVID-19 patients would be 3-6 times greater, which in turn would trigger severe adverse and possible toxic effects, specifically nephrotoxicity[ 32 ].…”

“…One of the issues is to reach adequate tissue level, as the key virus load is in the respiratory tract and lungs rather than in serum and the cyclosporine concentration in the lungs is lesser than in serum[ 32 ]. Additionally, the necessary dosage for vigorously treating severe COVID-19 patients would be 3-6 times greater, which in turn would trigger severe adverse and possible toxic effects, specifically nephrotoxicity[ 32 ]. Inhaled cyclosporine has been tried in animals, healthy volunteers and pulmonary transplantation recipients and the pulmonary amount of inhaled cyclosporine is three times more than when systemically administered[ 32 ].…”