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In Silico Evaluation of Cyclophilin Inhibitors as Potential Treatment for SARS-CoV-2.
Laurie, Kyle; Holcomb, David; Kames, Jacob; Komar, Anton A; DiCuccio, Michael; Ibla, Juan C; Kimchi-Sarfaty, Chava.
  • Laurie K; Center for Biologics Evaluation and Research, Office of Tissues and Advanced Therapies, Division of Plasma Protein Therapeutics, Food and Drug Administration, Silver Spring, Maryland, USA.
  • Holcomb D; Center for Biologics Evaluation and Research, Office of Tissues and Advanced Therapies, Division of Plasma Protein Therapeutics, Food and Drug Administration, Silver Spring, Maryland, USA.
  • Kames J; Center for Biologics Evaluation and Research, Office of Tissues and Advanced Therapies, Division of Plasma Protein Therapeutics, Food and Drug Administration, Silver Spring, Maryland, USA.
  • Komar AA; Center for Gene Regulation in Health and Disease, Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, Ohio, USA.
  • DiCuccio M; National Center of Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.
  • Ibla JC; Division of Cardiac Anesthesia, Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Kimchi-Sarfaty C; Center for Biologics Evaluation and Research, Office of Tissues and Advanced Therapies, Division of Plasma Protein Therapeutics, Food and Drug Administration, Silver Spring, Maryland, USA.
Open Forum Infect Dis ; 8(6): ofab189, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1263681
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.
Keywords

Full text: Available Collection: International databases Database: MEDLINE Type of study: Experimental Studies / Prognostic study Language: English Journal: Open Forum Infect Dis Year: 2021 Document Type: Article Affiliation country: Ofid

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Experimental Studies / Prognostic study Language: English Journal: Open Forum Infect Dis Year: 2021 Document Type: Article Affiliation country: Ofid