Cyclophilins and cyclophilin inhibitors in nidovirus replication

Abstract

Cyclophilins (Cyps) belong to the family of peptidyl-prolyl isomerases (PPIases). The PPIase activity of most Cyps is inhibited by the immunosuppressive drug cyclosporin A and several of its non-immunosuppressive analogs, which can also block the replication of nidoviruses (arteriviruses and coronaviruses). Cyclophilins have been reported to play an essential role in the replication of several other RNA viruses, including human immunodeficiency virus-1, hepatitis C virus, and influenza A virus. Likewise, the replication of various nidoviruses was reported to depend on Cyps or other PPIases. This review summarizes our current understanding of this class of nidovirus-host interactions, including the potential function of in particular CypA and the inhibitory effect of Cyp inhibitors. Also the involvement of the FK-506-binding proteins and parvulins is discussed. The nidovirus data are placed in a broader perspective by summarizing the most relevant data on Cyp interactions and Cyp inhibitors for other RNA viruses.

Keywords: Alisporivir; Arterivirus; Coronavirus; Cyclophilin A; Cyclosporin A; FK-506-binding proteins; NIM-811; Parvulins; RNA virus.

Fig. 1

Schematic overview of the presumed role of cyclophilins, FK-506 binding proteins and parvulins in nidovirus replication, as well as the effect of related inhibitors. Blue arrows indicate processes or interactions that positively affect virus replication. In red, inhibitory effects on infection are indicated that are induced by chemical inhibitors, protein-inhibitor complexes, or protein-protein complexes. See chapter 2 and chapter 3 for more details. Abbreviations: gRNA (+), positive-stranded genomic nidovirus RNA; pp1a, polyprotein 1a; pp1ab, polyprotein 1ab; RC, replication complex; Caln, calcineurin; CsA, cyclosporin A; Cyp, cyclophilin; FKBP, FK-506 binding protein; Pin-1, Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1; CypI, cyclophilin inhibitors; MPTP, mitochondrial permeability transition pore; nsp, nonstructural protein; IL-2, interleukin-2; DTM, dipentamethylene thiuram monosulfide; P, phosphate; NF-AT, nuclear factor of activated T-cells.