Influenza A(H1N1)pdm09 virus resistance to baloxavir, oseltamivir and sialic acid mimetics in single and dual therapies : Insights from human airway epithelia and murine models

Article Article scientifique Article Influenza A(H1N1)pdm09 virus resistance to baloxavir, oseltamivir and sialic acid mimetics in single and dual therapies : Insights from human airway epithelia and murine models eng 2025-05-03 2025-07 author Fage Clément Department of Microbiology and Molecular Medicine, University of Geneva, 1 Rue Michel-Servet, 1206, Geneva, Switzerland. 982808 author Loison Sheryline Department of Microbiology and Molecular Medicine, University of Geneva, 1 Rue Michel-Servet, 1206, Geneva, Switzerland. 403878 Département de microbiologie et médecine moléculaire (MIMOL) author Zwygart Arnaud Charles-Antoine Department of Microbiology and Molecular Medicine, University of Geneva, 1 Rue Michel-Servet, 1206, Geneva, Switzerland. 849319 Département de microbiologie et médecine moléculaire (MIMOL) author Poli Romain Department of Microbiology and Molecular Medicine, University of Geneva, 1 Rue Michel-Servet, 1206, Geneva, Switzerland. 974142 author Rosset Stéphane Department of Microbiology and Molecular Medicine, University of Geneva, 1 Rue Michel-Servet, 1206, Geneva, Switzerland. 810554 Département de microbiologie et médecine moléculaire (MIMOL) author Medaglia Chiara Department of Microbiology and Molecular Medicine, University of Geneva, 1 Rue Michel-Servet, 1206, Geneva, Switzerland. 912920 author Hubert Mathieu Department of Microbiology and Molecular Medicine, University of Geneva, 1 Rue Michel-Servet, 1206, Geneva, Switzerland. 418798 Département de microbiologie et médecine moléculaire (MIMOL) author Suter Boquete Patricia Geneva Center for Emerging Viral Diseases, Swiss National Reference Center of Influenza, Geneva University Hospitals, Geneva, Switzerland. 649426 author Vadas Oscar 0000-0003-3511-6479 Protein Biochemistry Platform, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 508966 Département de microbiologie et médecine moléculaire (MIMOL) author Huang Song Epithelix Sarl, 18 chemin des Aulx, 1228, Plan-les-Ouates, Switzerland. 123851 author Constant Samuel Claude Epithelix Sarl, 18 chemin des Aulx, 1228, Plan-les-Ouates, Switzerland. 543250 author Silva Paulo Institute of Materials, École polytechnique fédérale de Lausanne, 1015, Lausanne, Switzerland. author Stellacci Francesco Institute of Materials, École polytechnique fédérale de Lausanne, 1015, Lausanne, Switzerland. author Clément Leboube Sophie Department of Microbiology and Molecular Medicine, University of Geneva, 1 Rue Michel-Servet, 1206, Geneva, Switzerland. 120543 Département de microbiologie et médecine moléculaire (MIMOL) Sophie Clément author Tapparel Caroline 0000-0002-0411-6567 Department of Microbiology and Molecular Medicine, University of Geneva, 1 Rue Michel-Servet, 1206, Geneva, Switzerland. Electronic address: caroline.tapparel@unige.ch. 27039 Département de microbiologie et médecine moléculaire (MIMOL) 106174 10.1016/j.antiviral.2025.106174 40324597 0166-3542 https://www.sciencedirect.com/science/article/pii/S0166354225001007 Influenza viruses pose a significant threat due to annual epidemics and pandemic potential. Resistance to current antivirals underscores the need for new drugs and strategies to prevent its emergence. We previously developed two novel HA-targeting compounds (CD-6'SLN and CD-SA) with demonstrated efficacy against influenza A and B strains. Here, we compared their resistance barrier to that of FDA-approved oseltamivir (OS) and baloxavir marboxil (BXM). We established a resistance testing assay in human airway epithelia (HAE) and in mice. We also evaluated the impact of combination therapies on resistance emergence. In HAE, highly reduced inhibition (HRI) by CD-6'SLN and CD-SA occurred within 2 and 4 weeks respectively without fitness loss, while reduced inhibition (RI) by baloxavir acid (BXA) emerged within 4 weeks. No reduction of susceptibility to OS was observed in the same time frame. Of note, emergence of RI by CD-SA was not delayed in BXA/CD-SA co-treatment, and slightly reduced upon OS/CD-SA co-treatment. In mice, RI by CD-SA was observed after 8 passages in one of three mice treated with OS/CD-SA, but not in mice with single therapies. This study demonstrates that (1) HAE represents a relevant model to detect emergence of resistance and (2) HA-targeting compounds are prone to induce resistance followed by BXA and OS. Importantly, combination of clinically available antivirals and HA-targeting compounds did not prevent the emergence of variants with HA substitutions. Additional research is needed to develop anti-influenza antivirals with high resistance barrier and compounds should be tested in HAE before moving to animal experimentation. Antiviral resistance Baloxavir Combination therapy Human airway epithelia Influenza virus Mice Oseltamivir Sialic acid mimetics Animals Drug Resistance, Viral Oseltamivir / pharmacology Antiviral Agents / pharmacology Humans Triazines / pharmacology Dibenzothiepins / pharmacology Influenza A Virus, H1N1 Subtype / drug effects Morpholines / pharmacology Pyridones / pharmacology Orthomyxoviridae Infections / drug therapy Orthomyxoviridae Infections / virology Disease Models, Animal Thiepins / pharmacology Influenza, Human / drug therapy Influenza, Human / virology Pyridines / pharmacology Drug Therapy, Combination N-Acetylneuraminic Acid / pharmacology Female Respiratory Mucosa / virology Dewey 616 Swiss National Science Foundation Novel virucidal drugs: From basic to in vivo studies 180323 CH 54 Département de microbiologie et médecine moléculaire 21B 56 Département de médecine 221 false 931 Identification des facteurs clés impliqués dans la pathogénèse des rhinovirus et entérovirus 953 443 Biologie d'un parasite intracellulaire obligatoire 773 Antiviral research 239 f4abcfc9-87b4-4ad0-b5fd-2473a37bb146 Article (Published version) Public Influenza.pdf 2512870 application/pdf CC BY-4.0 fa6657187baa186d8edc18ab7f108622cc073079ca29f8bcce2d3b5daa3d4d57 8c7b2316-c0a3-430a-987a-5b837dbf287b Supplemental data Public 1-s2.0-S0166354225001007-mmc1-1.docx 979166 application/vnd.openxmlformats-officedocument.wordprocessingml.document a09668193b30fda79e7458b8f596c63ef38c0dc4213760c0a1153ef900bd8ea9 openAccess Faculté de médecine / Section de médecine fondamentale / Département de microbiologie et médecine moléculaire Faculté de médecine / Section de médecine clinique / Département de médecine

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Influenza A(H1N1)pdm09 virus resistance to baloxavir, oseltamivir and sialic acid mimetics in single and dual therapies : Insights from human airway epithelia and murine models	Antiviral research	2025	9	48
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Rosset, Stéphane