The Cyclophilin-Dependent Calcineurin Inhibitor Voclosporin Inhibits SARS-CoV-2 Replication in Cell Culture.

Autor:	Ogando NS; Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands., Metscher E; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, Netherlands., Moes DJAR; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, Netherlands.; Leiden Transplant Center, Leiden University Medical Center, Leiden, Netherlands., Arends EJ; Department of Nephrology, Leiden University Medical Center, Leiden, Netherlands., Tas A; Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands., Cross J; Aurinia Pharmaceuticals Inc., Victoria, BC, Canada., Snijder EJ; Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands., Teng YKO; Leiden Transplant Center, Leiden University Medical Center, Leiden, Netherlands.; Department of Nephrology, Leiden University Medical Center, Leiden, Netherlands., de Vries APJ; Leiden Transplant Center, Leiden University Medical Center, Leiden, Netherlands.; Department of Nephrology, Leiden University Medical Center, Leiden, Netherlands., van Hemert MJ; Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands.
Jazyk:	angličtina
Zdroj:	Transplant international : official journal of the European Society for Organ Transplantation [Transpl Int] 2022 Jun 24; Vol. 35, pp. 10369. Date of Electronic Publication: 2022 Jun 24 (Print Publication: 2022).
DOI:	10.3389/ti.2022.10369
Abstrakt:	Kidney transplant recipients (KTRs) are at increased risk for a more severe course of COVID-19, due to their pre-existing comorbidity and immunosuppression. Consensus protocols recommend lowering immunosuppression in KTRs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the optimal combination remains unclear. Calcineurin inhibitors (CNIs) are cornerstone immunosuppressants used in KTRs and some have been reported to possess antiviral activity against RNA viruses, including coronaviruses. Here, we evaluated the effect of the CNIs tacrolimus, cyclosporin A, and voclosporin (VCS), as well as other immunosuppressants, on SARS-CoV-2 replication in cell-based assays. Unexpected, loss of compound due to plastic binding and interference of excipients in pharmaceutical formulations (false-positive results) complicated the determination of EC50 values of cyclophilin-dependent CNI's in our antiviral assays. Some issues could be circumvented by using exclusively glass lab ware with pure compounds. In these experiments, VCS reduced viral progeny yields in human Calu-3 cells at low micromolar concentrations and did so more effectively than cyclosporin A, tacrolimus or other immunosuppressants. Although, we cannot recommend a particular immunosuppressive regimen in KTRs with COVID-19, our data suggest a potential benefit of cyclophilin-dependent CNIs, in particular VCS in reducing viral progeny, which warrants further clinical evaluation in SARS-CoV-2-infected KTRs. Competing Interests: This is investigator-initiated research. JC is an employee of Aurinia Pharmaceuticals Inc. YT received a grant without restrictions from Aurinia Pharmaceuticals Inc. to support part of this project and is an investigator of Aurinia clinical trials. Aurinia Pharmaceuticals Inc. had no role in the decision (what and when) to publish. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Ogando, Metscher, Moes, Arends, Tas, Cross, Snijder, Teng, de Vries and van Hemert.)
Databáze:	MEDLINE
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