2. Academic Validation
  3. Synergistic combination of orally available safe-in-man pleconaril, AG7404, and mindeudesivir inhibits enterovirus infections in human cell and organoid cultures

Synergistic combination of orally available safe-in-man pleconaril, AG7404, and mindeudesivir inhibits enterovirus infections in human cell and organoid cultures

  • Cell Mol Life Sci. 2025 Jan 23;82(1):57. doi: 10.1007/s00018-025-05581-4.
Erlend Ravlo # 1,  Aleksandr Ianevski # 1,  Jørn-Ove Schjølberg 1 2,  Vanessa Solvang 1,  Rabina Dumaru 1,  Hilde Lysvand 1,  Jacqueline Hankinson 3,  Markus Vähä-Koskela 4 5 6,  Sanna Vainionpää 5 6 7,  Anni Varhe 5 6 7,  Hanna Seppänen 5 6 7,  Teemu Smura 8 9,  Xin Wang 10,  Yining Wang 10,  Pengfei Li 10,  Qiuwei Pan 10,  Knut Dahl-Jorgensen 11,  Lars Krogvold 12,  Oleksandr Kamyshnyi 13,  Hans-Johnny Schjelderup Nilsen 14,  Inger Johanne Haugen 14,  Erling Høyer 14,  Jan Egil Afset 14,  Valentyn Oksenych 15,  Angel S Galabov 16,  Adelina Stoyanova 16,  Vivian Lam 17,  Barbara van Loon 1,  Valeria Lulla 3,  Magnar Bjørås 18 19 20,  Denis E Kainov 21 22
Affiliations

Affiliations

  • 1 Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, Trondheim, 7028, Norway.
  • 2 Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, 0372, Norway.
  • 3 Department of Pathology, University of Cambridge, Cambridge, CB21QP, UK.
  • 4 Institute for Molecular Medicine FIMM, Helsinki Institute for Life Science, University of Helsinki, Helsinki, 00014, Finland.
  • 5 Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, 00014, Finland.
  • 6 iCAN Digital Precision Cancer Medicine Flagship, Helsinki, 00014, Finland.
  • 7 Department of Surgery, Helsinki University Hospital, Helsinki, Finland.
  • 8 Department of Virology, University of Helsinki, Helsinki, 00014, Finland.
  • 9 Clinical Microbiology, Helsinki University Hospital, HUS Diagnostic Center, University of Helsinki, Helsinki, 00029, Finland.
  • 10 Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, 3015, Netherlands.
  • 11 Faculty of Medicine, University of Oslo, Oslo, 0318, Norway.
  • 12 Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, 0424, Norway.
  • 13 Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, Ternopil, 46001, Ukraine.
  • 14 Department of Medical Microbiology, Clinic for Laboratory Medicine, St. Olavs Hospital, Trondheim, 7028, Norway.
  • 15 Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, 5021, Norway.
  • 16 The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, 1113, Bulgaria.
  • 17 LHL, Jessheim, 2067, Norway.
  • 18 Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, Trondheim, 7028, Norway. magnar.bjoras@ntnu.no.
  • 19 Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, 0372, Norway. magnar.bjoras@ntnu.no.
  • 20 Centre for Embryology and Healthy Development (CRESCO), University of Oslo, Oslo, 0373, Norway. magnar.bjoras@ntnu.no.
  • 21 Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, Trondheim, 7028, Norway. denis.kainov@ntnu.no.
  • 22 Institute for Molecular Medicine FIMM, Helsinki Institute for Life Science, University of Helsinki, Helsinki, 00014, Finland. denis.kainov@ntnu.no.
  • # Contributed equally.
PMID: 39843710 DOI: 10.1007/s00018-025-05581-4
Abstract

Enteroviruses can infect various human organs, causing diseases such as meningitis, the common cold, hand-foot-and-mouth disease, myocarditis, pancreatitis, hepatitis, poliomyelitis, sepsis, and type 1 diabetes. Currently, there are no approved treatments for Enterovirus infections. In this study, we identified a synergistic combination of orally available, safe-in-man pleconaril, AG7404, and mindeudesivir, that at non-toxic concentrations effectively inhibited Enterovirus replication in human cell and Organoid cultures. Importantly, the cocktail did not alter glucose and Insulin levels in the culture medium of pancreatic β-cells and preserved the contraction rhythm of infected heart organoids. These findings highlight a promising drug cocktail for further preclinical studies and clinical trials targeting a broad range of enterovirus-mediated diseases.

Keywords

Antiviral drug combination; Broad-spectrum antivirals; Drug synergy; Enterovirus.

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