Broad-Spectrum Antiviral Activity of Cyclophilin Inhibitors Against Coronaviruses: A Systematic Review

Cyclophilins (Cyps), a family of peptidyl-prolyl isomerases, play essential roles in the life cycle of coronaviruses by interacting with viral proteins and modulating host immune responses. In this systematic review, we examined cell culture, animal model, and clinical studies assessing the anti-viral efficacy of cyclosporine A (CsA, PubChem CID: 5284373) and its non-immunosuppressive derivatives against coronaviruses. CsA demonstrated robust anti-viral activity in vitro across a broad range of coronaviruses, including but not limited to HCoV-229E, SARS-CoV, MERS-CoV, and SARS-CoV-2, with potent EC₅₀ values in the low micromolar range. Non-immunosuppressive analogs such as Alisporivir and NIM811 exhibited similar inhibitory effects. In vivo, CsA treatment significantly reduced viral load, ameliorated lung pathology, and improved survival in coronavirus-infected animals. Clinical studies further indicated that CsA administration was associated with improved outcomes in COVID-19 patients, including reduced mortality and shorter hospital stays. Mechanistic studies revealed that CsA disrupts the formation of viral replication complexes, interferes with critical Cyp-viral protein interactions, and modulates innate immune signaling. These findings collectively demonstrate the therapeutic potential of cyclophilin inhibitors as broad-spectrum anti-virals against current and emerging coronaviruses.