In Silico Evaluation of Cyclophilin Inhibitors as Potential Treatment for SARS-CoV-2

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Open Forum Infect Dis. 2021 Apr 14;8(6):ofab189. doi: 10.1093/ofid/ofab189. eCollection 2021 Jun.

ABSTRACT

BACKGROUND: The advent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provoked researchers to propose multiple antiviral strategies to improve patients’ outcomes. Studies provide evidence that cyclosporine A (CsA) decreases SARS-CoV-2 replication in vitro and decreases mortality rates of coronavirus disease 2019 (COVID-19) patients. CsA binds cyclophilins, which isomerize prolines, affecting viral protein activity.

METHODS: We investigated the proline composition from various coronavirus proteomes to identify proteins that may critically rely on cyclophilin’s peptidyl-proline isomerase activity and found that the nucleocapsid (N) protein significantly depends on cyclophilin A (CyPA). We modeled CyPA and N protein interactions to demonstrate the N protein as a potential indirect therapeutic target of CsA, which we propose may impede coronavirus replication by obstructing nucleocapsid folding.

RESULTS: Finally, we analyzed the literature and protein-protein interactions, finding evidence that, by inhibiting CyPA, CsA may impact coagulation proteins and hemostasis.

CONCLUSIONS: Despite CsA’s promising antiviral characteristics, the interactions between cyclophilins and coagulation factors emphasize risk stratification for COVID patients with thrombosis dispositions.

PMID:34109257 | PMC:PMC8083350 | DOI:10.1093/ofid/ofab189