Itraconazole for COVID-19

ABSTRACT Severe COVID‐19 cases are often characterised by a hyperinflammatory cytokine storm, which leads to immune dysregulation and increased mortality. Simultaneously, opportunistic fungal infections such as mucormycosis have been increasingly reported, especially in immunocompromised individuals. Triazole antifungals are widely used to treat such infections, but their potential immunomodulatory effects remain underexplored. This study aimed to investigate the off‐target potential of commonly used antifungal triazoles itraconazole, ketoconazole, posaconazole and voriconazole against human phosphodiesterase‐4 (PDE‐4), a key enzyme involved in the regulation of pro‐inflammatory cytokine expression. To our knowledge, this is the first study to explicitly propose and computationally validate the dual role of triazole antifungals as both antifungal and immunomodulatory agents. A computational approach comprising molecular docking, molecular dynamics (MD) simulations and quantum chemical analysis was employed to evaluate the interaction of the selected triazoles with PDE‐4. Binding affinity and interaction stability were compared with roflumilast, a known PDE‐4 inhibitor. Among the tested triazoles, posaconazole exhibited the most favourable binding energy (−44.60 kcal/mol via MM‐GBSA), forming stable interactions with key residues in the catalytic site of PDE‐4, similar to those observed with roflumilast. MD simulations further confirmed the binding stability of posaconazole, as evidenced by favourable RMSD and hydrogen bonding patterns. Quantum chemical analysis indicated strong electrophilicity and reactivity of posaconazole, supporting its potential PDE‐4 inhibitory activity. The findings suggest that certain triazole antifungals, especially posaconazole, may both fight fungal infections and reduce the cytokine storm in severe COVID‐19, offering a promising rapid‐response therapeutic strategy.

The rapid development of vaccines to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has been critical to reduce the severity of COVID-19. However, the continuous emergence of new SARS-CoV-2 subtypes highlights the need to develop additional approaches that oppose viral infections. Targeting host factors that support virus entry, replication, and propagation provide opportunities to lower SARS-CoV-2 infection rates and improve COVID-19 outcome. This includes cellular cholesterol, which is critical for viral spike proteins to capture the host machinery for SARS-CoV-2 cell entry. Once endocytosed, exit of SARS-CoV-2 from the late endosomal/lysosomal compartment occurs in a cholesterol-sensitive manner. In addition, effective release of new viral particles also requires cholesterol. Hence, cholesterol-lowering statins, proprotein convertase subtilisin/kexin type 9 antibodies, and ezetimibe have revealed potential to protect against COVID-19. In addition, pharmacological inhibition of cholesterol exiting late endosomes/lysosomes identified drug candidates, including antifungals, to block SARS-CoV-2 infection. This review describes the multiple roles of cholesterol at the cell surface and endolysosomes for SARS-CoV-2 entry and the potential of drugs targeting cholesterol homeostasis to reduce SARS-CoV-2 infectivity and COVID-19 disease severity.

Since the beginning of the COVID-19 pandemic, extensive drug repurposing efforts have sought to identify small-molecule antivirals with various mechanisms of action. Here, we aim to review research progress on small-molecule viral entry and fusion inhibitors that directly bind to the SARS-CoV-2 Spike protein. Early in the pandemic, numerous small molecules were identified in drug repurposing screens and reported to be effective in in vitro SARS-CoV-2 viral entry or fusion inhibitors. However, given minimal experimental information regarding the exact location of small-molecule binding sites on Spike, it was unclear what the specific mechanism of action was or where the exact binding sites were on Spike for some inhibitor candidates. The work of countless researchers has yielded great progress, with the identification of many viral entry inhibitors that target elements on the S1 receptor-binding domain (RBD) or N-terminal domain (NTD) and disrupt the S1 receptor-binding function. In this review, we will also focus on highlighting fusion inhibitors that target inhibition of the S2 fusion function, either by disrupting the formation of the postfusion S2 conformation or alternatively by stabilizing structural elements of the prefusion S2 conformation to prevent conformational changes associated with S2 function. We highlight experimentally validated binding sites on the S1/S2 interface and on the S2 subunit. While most substitutions to the Spike protein to date in variants of concern (VOCs) have been localized to the S1 subunit, the S2 subunit sequence is more conserved, with only a few observed substitutions in proximity to S2 binding sites. Several recent small molecules targeting S2 have been shown to have robust activity over recent VOC mutant strains and/or greater broad-spectrum antiviral activity for other more distantly related coronaviruses.

AbstractTo attain promising pharmacotherapies, researchers have applied drug repurposing (DR) techniques to discover the candidate medicines to combat the coronavirus disease 2019 (COVID-19) outbreak. Although many DR approaches have been introduced for treating different diseases, only structure-based DR (SBDR) methods can be employed as the first therapeutic option against the COVID-19 pandemic because they rely on the rudimentary information about the diseases such as the sequence of the severe acute respiratory syndrome coronavirus 2 genome. Hence, to try out new treatments for the disease, the first attempts have been made based on the SBDR methods which seem to be among the proper choices for discovering the potential medications against the emerging and re-emerging infectious diseases. Given the importance of SBDR approaches, in the present review, well-known SBDR methods are summarized, and their merits are investigated. Then, the databases and software applications, utilized for repurposing the drugs against COVID-19, are introduced. Besides, the identified drugs are categorized based on their targets. Finally, a comparison is made between the SBDR approaches and other DR methods, and some possible future directions are proposed.