Synergistic combination of orally available safe-in-man pleconaril, AG7404, and mindeudesivir inhibits enterovirus infections in human cell and organoid cultures
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.
Authors
- Knut Dahl‐Jørgensen (ORCID: https://orcid.org/0000-0002-6952-9899)
- Denis E. Kainov (ORCID: https://orcid.org/0000-0001-7716-6955)
- Valeria Lulla (ORCID: https://orcid.org/0000-0002-6605-0727)
- Magnar Bjørås (ORCID: https://orcid.org/0000-0001-8759-1170)
- Erlend Ravlo
- Valentyn Oksenych (ORCID: https://orcid.org/0000-0002-5088-3791)
- Markus Vähä‐Koskela (ORCID: https://orcid.org/0000-0001-7764-7820)
- Sanna Vainionpää
- Teemu Smura (ORCID: https://orcid.org/0000-0002-9187-3151)
- Barbara van Loon (ORCID: https://orcid.org/0000-0002-7597-207X)
- Hilde Lysvand
- Qiuwei Pan (ORCID: https://orcid.org/0000-0001-9982-6184)
- Anu Varhe
- Hanna Seppänen (ORCID: https://orcid.org/0000-0002-2529-651X)
- Xin Wang (ORCID: https://orcid.org/0000-0003-0644-481X)
- Angel S. Galabov (ORCID: https://orcid.org/0000-0001-8554-1655)
- Oleksandr Kamyshnyi (ORCID: https://orcid.org/0000-0003-3141-4436)
- Aleksandr Ianevski (ORCID: https://orcid.org/0000-0002-7780-482X)
- Jan Egil Afset (ORCID: https://orcid.org/0000-0003-2489-4179)
- Hans-Johnny Schjelderup Nilsen (ORCID: https://orcid.org/0000-0002-1749-0654)
- Lars Krogvold (ORCID: https://orcid.org/0000-0002-1057-7095)
- Jørn-Ove Schjølberg
- Vanessa Solvang
- Erling Høyer
- Rabina Dumaru
- Yining Wang (ORCID: https://orcid.org/0000-0001-6441-2002)
- I.K. Haugen (ORCID: https://orcid.org/0000-0001-7810-2216)
- Pengfei Li
- Adelina Stoyanova (ORCID: https://orcid.org/0000-0002-6401-2997)
- Jacqueline Hankinson (ORCID: https://orcid.org/0000-0002-3107-1501)
- Vivian Lam
Institutions
- Oslo University Hospital (NO)
- University of Helsinki (FI)
- University of Oslo (NO)
- Norwegian University of Science and Technology (NO)
- University of Cambridge (GB)
- Bulgarian Academy of Sciences (BG)
- Helsinki University Hospital (FI)
- Erasmus MC (NL)
- St Olav's University Hospital (NO)
- Stephan Angeloff Institute of Microbiology (BG)
- Institute for Molecular Medicine Finland (FI)
- I.Horbachevsky Ternopil National Medical University (UA)
- University of Bergen (NO)
Publication Details
- Journal
- Cellular and Molecular Life Sciences
- Published
- 2025-01-23
- DOI
- https://doi.org/10.1007/s00018-025-05581-4
- Citations
- 5
- Primary Topic
- Viral Infections and Immunology Research
- Type
- article
- Field-Weighted Citation Impact
- 6.94
Funders
- Norges Teknisk-Naturvitenskapelige Universitet
- Wellcome Trust
- European Commission
- Helse Midt-Norge
- St. Olavs Hospital Universitetssykehuset i Trondheim
- Medical Research Council