In Silico Evaluation of Cyclophilin Inhibitors as Potential Treatment for SARS-CoV-2. (14th April 2021)

• Record Type: Journal Article
• Authors: Laurie, Kyle; Holcomb, David; Kames, Jacob; Komar, Anton A; DiCuccio, Michael; Ibla, Juan C; Kimchi-Sarfaty, Chava
• Is Part Of: Open forum infectious diseases. Volume 8:Number 6(2021)
• Publication Date: 2021-04-14
• Subjects: ADAMTS13 -- antiviral -- coagulopathy -- COVID-19 -- cyclophilin -- cyclosporine A; Communicable diseases -- Periodicals; Medical microbiology -- Periodicals; Infection -- Periodicals; 616.9
• DOI: 10.1093/ofid/ofab189
• Languages: English
• ISSNs: 2328-8957

Abstract

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.