4.10. Cyclosporine A (Gengraf)
Cyclosporine A is a cyclic peptide that is naturally obtained from the fungus Beauveria nivea [191]. It is immunosuppressant and calcineurin inhibitor that inhibits T cell activation [192]. It binds to the intracellular receptor cyclophilin-1 producing a cyclosporine-cyclophilin complex. This complex subsequently inhibits calcineurin, which stops the activation of the nuclear factor of activated T cells (NF-AT) that normally causes inflammatory reactions. The inhibition of NF-AT also leads to lower levels of other factors associated with T helper cell function and thymocyte development. Cyclosporine was first approved by the U.S. FDA in 1983 and is orally, parenterally, or topically used to prevent organ transplant rejection, treat/prevent graft-versus-host disease, and treat various inflammatory and autoimmune conditions such as severe rheumatoid arthritis and psoriasis [191,192,193,194,195].
Importantly, low micromolar concentrations of cyclosporin A (<35 µM) substantially impacted the replication of SARS-CoV, human coronavirus 229E, and mouse hepatitis virus in cell culture. Cyclosporin A significantly inhibited gene expression and reduced progeny titers. Cyclosporin A treatment completely blocked SARS-CoV RNA and protein synthesis [196]. Cyclosporine A also in vitro reduced the replication of MERS-CoV, transmissible gastroenteritis coronavirus, porcine epidemic diarrhea virus, and feline coronavirus [196]. In fact, cyclosporine A has demonstrated broad-spectrum antiviral effects. It inhibited the replication of HBV, HCV, and HIV [197]. Cyclosporine also inhibited the replication of Zika virus, West Nile virus, Rift Valley fever virus, and influenza A virus by blocking the interaction of cellular cyclophilins with viral proteins as well as by inhibiting the RNA synthesis [198]. By targeting cyclophilins, the drug can also prevent acute lung injury [199]. Currently, the use of cyclosporin A is being tested in patients with moderate COVID-19 (NCT04412785; n = 20), hospitalized COVID-19 patients (NCT04392531; n = 120), and combined with topical corticosteroid in COVID-19 patients with acute keratoconjunctivitis (NCT04451239; n = 12). It has also been used in psoriatic COVID-19 patients [200].