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Spondweni virus infects humans to cause febrile illness which is similar to Zika virus infection. Both viruses have almost similar NS5 protein which interacts with host cyclophilin protein to cause the disease. Cyclophilin is a member of cellular peptidyl-prolylisomerase (PPIase) family, which plays a role in flavivirus replication. The immunosuppressant drug cyclosporine inhibits the flavivirus replication by blocking the interaction between host cyclophilin and viral NS5 protein. As no specific treatment is available to prevent Spondweni virus infection, we have investigated the in silico therapeutic potential of two selected immunosuppressant drugs cyclosporine A and isogarcinol (CID 5284373; 11135781) against Spondweni infection using molecular docking analysis. The 3D model of Spondweni virus NS5 protein region (YP_009222008.1:2532-3413) was predicted using Zika virus NS5 model (PDB ID: 5TFR with query coverage 99% and identity 78%) as template. Further in silico docking interaction was performed to investigate the residues involved in interaction. The interaction of cyclosporine A and isogarcinol with the target protein of Spondweni virus suggested that both immunosuppressants interacted with prominent binding site with good docking score and might be involved in blocking the binding of host cyclophilin to Spondweni virus protein. Thus both immunosuppressants cyclosporine A and isogarcinol can be explored as a promising drug for the prevention of Spondweni virus infection. When both immunosuppressants are compared, cyclosporine A might act better than isogarcinol and have greater therapeutic potential against Spondweni virus disease.