Effects of Drugs Formerly Suggested for COVID-19 Repurposing on Pannexin1 Channels.

Although many efforts have been made to elucidate the pathogenesis of COVID-19, the underlying mechanisms are yet to be fully uncovered. However, it is known that a dysfunctional immune response and the accompanying uncontrollable inflammation lead to troublesome outcomes in COVID-19 patients. Pannexin1 channels are put forward as interesting drug targets for the treatment of COVID-19 due to their key role in inflammation and their link to other viral infections. In the present study, we selected a panel of drugs previously tested in clinical trials as potential candidates for the treatment of COVID-19 early on in the pandemic, including hydroxychloroquine, chloroquine, azithromycin, dexamethasone, ribavirin, remdesivir, favipiravir, lopinavir, and ritonavir. The effect of the drugs on pannexin1 channels was assessed at a functional level by means of measurement of extracellular ATP release. Immunoblot analysis and real-time quantitative reversetranscription polymerase chain reaction analysis were used to study the potential of the drugs to alter pannexin1 protein and mRNA expression levels, respectively. Favipiravir, hydroxychloroquine, lopinavir, and the combination of lopinavir with ritonavir were found to inhibit pannexin1 channel activity without affecting pannexin1 protein or mRNA levels. Thusthree new inhibitors of pannexin1 channels were identified that, though currently not being used anymore for the treatment of COVID-19 patients, could be potential drug candidates for other pannexin1-related diseases.

Possible role of pannexin 1 channels and purinergic receptors in the pathogenesis and mechanism of action of SARS-CoV-2 and therapeutic potential of targeting them in COVID-19.

Identifying signaling pathways and molecules involved in SARS-CoV-2 pathogenesis is pivotal for developing new effective therapeutic or preventive strategies for COVID-19. Pannexins (PANX) are ATP-release channels in the plasma membrane essential in many physiological and immune responses. Activation of pannexin channels and downstream purinergic receptors play dual roles in viral infection, either by facilitating viral replication and infection or inducing host antiviral defense. The current review provides a hypothesis demonstrating the possible contribution of the PANX1 channel and purinergic receptors in SARS-CoV-2 pathogenesis and mechanism of action. Moreover, we discuss whether targeting these signaling pathways may provide promising preventative therapies and treatments for patients with progressive COVID-19 resulting from excessive pro-inflammatory cytokines and chemokines production. Several inhibitors of this pathway have been developed for the treatment of other viral infections and pathological consequences. Specific PANX1 inhibitors could be potentially included as part of the COVID-19 treatment regimen if, in future, studies demonstrate the role of PANX1 in COVID-19 pathogenesis. Of note, any ATP therapeutic modulation for COVID-19 should be carefully designed and monitored because of the complex role of extracellular ATP in cellular physiology.