Inhibition of vaccinia virus replication by cyclosporin A analogues correlates with their affinity for cellular cyclophilins

The mechanism by which cyclosporin A (CsA) inhibits vaccinia virus (VV) replication is still unclear. The present study addresses the question of whether CsA-binding proteins named cyclophilins (Cyps) are involved in the anti-VV activity of CsA. Six CsA analogues were analysed, and their affinity for Cyps in W-infected BSC-40 cells and their potency as inhibitors of VV replication were evaluated. It was demonstrated that analogues with strong Cyp-binding activity, such as CsC, CsG and [MeAla(6)]CsA, also exhibit a strong antiviral effect. In contrast, drugs with low ([MeBm(2)t(1)]CsA and CsH) or no ([MeLeu(11)]CsA) affinity for Cyps show poor or no antiviral activity. The data obtained suggest a correlation between the ability of CsA to block VV replication and Cyp binding activity, and indicate the involvement of Cyps in the VV replicative cycle. they also suggest that the anti-VV action of CsA may occur by a pathway distinct from that involved in the immunosuppressive effect of the drug.