Synergistic combination of orally available safe-in-man pleconaril, AG7404, and mindeudesivir inhibits enterovirus infections in human cell and organoid cultures PMID: 39843710

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
19. Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, 0372, Norway. [email protected].
20. Centre for Embryology and Healthy Development (CRESCO), University of Oslo, Oslo, 0373, Norway. [email protected].
21. Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, Trondheim, 7028, Norway. [email protected].
22. Institute for Molecular Medicine FIMM, Helsinki Institute for Life Science, University of Helsinki, Helsinki, 00014, Finland. [email protected].
# Contributed equally.

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.