The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continue   to evolve with no approved treatment or vaccines yet. Itraconazole (ITZ) is a broad-spectrum triazole antifungal  with  recently indicated  antiviral activity. Shim et al. reported the therapeutic and prophylactic function of  ITZ   against the human rhinovirus (HRV)  infection ,  a major causative organism of human respiratory tract infection,    in a murine model.  In this setting, ITZ act through decreasing  the level of   pro-inflammatory cytokines and chemokines induced by HRV infection including  IL-6, TNF-α , IL-1β , CXCL1/KC, and CCL2 ,correlating with reduced viral load. ITZ improved the histological acute lung inflammatory changes, particularly the neutrophils infiltrate , pulmonary edema, and hemorrhage (1). ITZ, by its action on CYP450 enzyme 5-lipooxigenase, interferes with the synthesis of leukotriene B4 (LTB4), the major product of arachidonic acid metabolism, which has been referred as a potent mediator of inflammatory processes and immunoregulation (2). This immunomodulatory role of  ITZ   could be beneficial against cytokine storm created by SARS-CoV-2 , which is  characterized by high levels of pro-inflammatory cytokines and chemokines ,particularly  CCL2 and TNFα  ,being significantly higher in patients requiring admission to intensive care units (3).  Additionally,  itraconazole  dramatically reduced the mortality and improved the survival from  the  Influenza A virus (IAV) ,  another common cause of respiratory tract infection , in vitro and  in vivo  utilizing  a mouse model, via a probable  mechanism of action  that  included  priming of the interferon response and the  imbalance of cellular cholesterol (4). Pulse therapy of itraconazole could significantly raise the serum level of IFN-γ secretion ,an important cytokine  which is crucial in antagonizing viral infections,  during and after treatment in seborrheic dermatitis patients (5).
Interestingly, itraconazole is supposed to be  a  potential inhibitor  of non-structural protein Nsp12, an RNA-dependent RNA polymerase (RdRp), which  has  a vital role in  coronavirus replication and transcription (6). In the research of SARS-CoV and MERS-CoV inhibitors,  Nsp12-RdRp has been used as a very important drug target  , due to the fact that active site of  RdRp is  highly conserved  ,strengthening its chance  as an anchor for inhibitory molecules (7) .Targeted inhibition of Nsp12-RdRp is proposed to be safe without  significant toxicity and adverse effects on host cells (8).
In an experimental model of pulmonary paracoccidioidomycosis,  itraconazole , alone or in combination with neutrophil depletion,   achieved  improvement of the inflammatory response and the pulmonary  fibrotic sequelae through the down-regulation of gene expression , such as IL-6, IL-10, IL-17 genes, associated with both inflammation and fibrosis process. This could point to ITZ importance in minimizing the risk of fibrotic lung disease if used in SARS-CoV-2 treatment (9).
Notably, combination of azithromycin, the widely used drug against SARS-CoV2, with antifungal agents, including itraconazole, could result in synergistic interactions with better therapeutic outcome (10). Therefore, itraconazole could be suggested in a new COVID-19 protocol and we could encourage  the enrollment of  this relatively cheap, available ,well tolerated drug for clinical trials to investigate its potential for COVID-19 treatment.
 
Abbreviations
ITZ: Itraconazole
COVID-19: Coronavrus Disease 2019
IL-6,10,17: Interleukin 6,10,17
TNF-α: Tumor necrosis factor alpha
IL-1β: Interleukin 1β
CXCL1/KC: Chemokine (C-X-C motif) ligand 1
CCL2: Chemokine (C-C motif) ligand 2
CYP450: Cytochrome P450
LTB4: Leukotriene B4
SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2
SARS-CoV: Severe acute respiratory syndrome coronavirus
MERS-CoV : Middle East respiratory syndrome coronavirus
RdRp: RNA-dependent RNA polymerase
Nsp12: Non-structural protein 12