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

Abstract

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.

Synthesis and Crystallization Research of Voclosporin

“…4,5 The clinical effects of Voclosporin in the treatment of dry eye and anti-COVID-19 have also been explored. 6,7 In order to facilitate the research and development of generic drugs, it is imperative to establish an efficient, largescale production process for Voclosporin. Multiple synthesis pathways were documented for this purpose.…”

“…For instance, Naicker et al reported a four-step synthesis method using allyltriphenylphosphonium bromide (5) as a Wittig reagent with an overall yield of 14.9% (Scheme 1). 8 However, the Wittig reaction yielded a ratio of the E isomer (6) to the Z isomer (7) at 45:55, necessitating the use of column chromatography separation to enhance the E isomer. Maeng et al explored the synthesis of Voclosporin through the application of organozirconium chemistry, employing a novel four-step procedure that yielded an overall yield of 42%.…”

“…Initially, it was described as a combination of cyclosporin’s terminal E - and Z -dienes. Further, it can be found in various distinct solid-state forms. , The clinical effects of Voclosporin in the treatment of dry eye and anti-COVID-19 have also been explored. , …”

The Mechanism and Potential Therapeutic Effects of Cyclosporin, Cyclophilin, Probiotics and Syndecan-1 in an Animal Model of Inflammatory Bowel Disease

“…In addition, the approach of using probiotics has been adopted in multiple instances with encouraging results both in animal and human studies but never in the presence of cyclosporine [ 10 ]. Cyclosporine A (CyA), an immunosuppressant that interacts with cytoplasmic cyclophilin A (CypA) [ 11 , 12 ], was introduced in the mid-1980s. In addition, probiotics have been used in the last two decades to correct dysbiosis [ 13 ].…”

Voclosporin and the Antiviral Effect Against SARS-CoV-2 in Immunocompromised Kidney Patients

“… 13 , 14 Moreover, there are several nonimmunosuppressive cyclosporin derivates that have potent suppressive effects on the replication of multiple coronaviruses. 15 , 16 In addition, 2 clinical cohort studies reported better outcomes in KTRs with a SARS-CoV-2 infection when CsA was part of their maintenance immunosuppression. 17 , 18 …”