Cyclosporine A for COVID-19

ABSTRACT SARS-CoV-2, the causative agent of COVID-19, has been intensely studied in search of effective antiviral treatments. The immunosuppressant cyclosporine A (CsA) has been suggested to be a pan-coronavirus inhibitor, yet its underlying mechanism remained largely unknown. Here, we found that non-structural protein 1 (Nsp1) of SARS-CoV-2 usurped CsA-suppressed nuclear factor of activated T cells (NFAT) signaling to drive the expression of cellular DEAD-box helicase 5 (DDX5), which facilitates viral replication. Nsp1 interacted with calcineurin A (CnA) to displace the regulatory protein regulator of calcineurin 3 (RCAN3) of CnA for NFAT activation. The influence of NFAT activation on SARS-CoV-2 replication was also validated by using the Nsp1-deficient mutant virus. Calcineurin inhibitors, such as CsA and VIVIT, inhibited SARS-CoV-2 replication and exhibited synergistic antiviral effects when used in combination with nirmatrelvir. Our study delineated the molecular mechanism of CsA-mediated inhibition of SARS-CoV-2 replication and the anti-SARS-CoV-2 action of calcineurin inhibitors. IMPORTANCE Cyclosporine A (CsA), commonly used to inhibit immune responses, is also known to have anti-SARS-CoV-2 activity, but its mode of action remains elusive. Here, we provide a model to explain how CsA antagonizes SARS-CoV-2 through three critical proteins: DDX5, NFAT1, and Nsp1. DDX5 is a cellular facilitator of SARS-CoV-2 replication, and NFAT1 controls the production of DDX5. Nsp1 is a viral protein absent from the mature viral particle and capable of activating the function of NFAT1 and DDX5. CsA and similar agents suppress Nsp1, NFAT1, and DDX5 to exert their anti-SARS-CoV-2 activity either alone or in combination with Paxlovid.

Abstract Background The active pursuit of network medicine for drug repurposing, particularly for combating Covid-19, has stimulated interest in the concept of structural controllability in cellular networks. We sought to extend this theory, focusing on the defense rather than control of the cell against viral infections. Accordingly, we extended structural controllability to total structural controllability and introduced the concept of control hubs. Perturbing any control hub may render the cell uncontrollable by exogenous stimuli like viral infections, so control hubs are ideal drug targets. Results We developed an efficient algorithm to identify all control hubs, applying it to a largest homogeneous network of human protein interactions, including interactions between human and SARS-CoV-2 proteins. Our method recognized 65 druggable control hubs with enriched antiviral functions. Utilizing these hubs, we categorized potential drugs into four groups: antiviral and anti-inflammatory agents, drugs acting on the central nervous system, dietary supplements, and compounds enhancing immunity. An exemplification of our approach’s effectiveness, Fostamatinib, a drug initially developed for chronic immune thrombocytopenia, is now in clinical trials for treating Covid-19. Preclinical trial data demonstrated that Fostamatinib could reduce mortality rates, ICU stay length, and disease severity in Covid-19 patients. Conclusions Our findings confirm the efficacy of our novel strategy that leverages control hubs as drug targets. This approach provides insights into the molecular mechanisms of potential therapeutics for Covid-19, making it a valuable tool for interpretable drug discovery. Our new approach is general and applicable to repurposing drugs for other diseases.