Inhibition of calcineurin or IMPDH exerts moderate to potent antiviral activity against norovirus replication [PublishAheadOfPrint]

Norovirus is a major cause of acute gastroenteritis worldwide and has emerged as an important issue of chronic infection in transplantation patients. Since no approved antiviral is available, we evaluated the effects of different immunosuppressants and ribavirin on norovirus and explored their mechanism-of-actions by using a human norovirus (HuNV) replicon-harboring model and a surrogate murine norovirus (MNV) infectious model. Roles of corresponding drug targets were investigated by gain- or loss-of-function approaches. We found calcineurin inhibitors cyclosporin A (CsA) and tacrolimus (FK506) moderately inhibited HuNV replication. Gene silencing of their cellular targets, cyclophilin A, FKBP12 and calcineurin, significantly inhibited HuNV replication. A therapeutically-speaking low concentration of mycophenolic acid (MPA), an uncompetitive inosine monophosphate dehydrogenase (IMPDH) inhibitor, potently and rapidly inhibited norovirus replication and ultimately cleared HuNV replicons without inducible resistance following long-term drug exposure. Knockdown of MPA cellular targets, IMPDH1 and IMPDH2, suppressed HuNV replication. Consistent with the nucleotide synthesizing function of IMPDH, exogenous guanosine counteracted the anti-norovirus effects of MPA. Furthermore, the competitive IMPDH inhibitor ribavirin efficiently inhibited norovirus and resulted in an additive effect when combined with immunosuppressants. The results from this study demonstrate that calcineurin phosphatase activity and IMPDH guanine synthase activity are crucial in sustaining norovirus infection, thus could be therapeutically targeted. Our results suggest that MPA shall be preferentially considered as immunosuppressive medication for transplantation patients at risk of norovirus infection; whereas ribavirin represents as a potential antiviral for both immunocompromised and immunocompetent patients with norovirus gastroenteritis.

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