Orally bioavailable RORγ/DHODH dual host-targeting small molecules with broad-spectrum antiviral activity

  • Antiviral Res. 2024 Sep 19:231:106008. doi: 10.1016/j.antiviral.2024.106008.
Alexandra Herrmann  1 ,  Christian Gege  2 ,  Christina Wangen  3 ,  Sabrina Wagner  4 ,  Melanie Kögler  5 ,  Arne Cordsmeier  6 ,  Pascal Irrgang  7 ,  Wing-Hang Ip  8 ,  Tatjana Weil  9 ,  Victoria Hunszinger  10 ,  Rüdiger Groß  11 ,  Natalie Heinen  12 ,  Stephanie Pfaender  13 ,  Sebastian Reuter  14 ,  Robert Klopfleisch  15 ,  Nadja Uhlig  16 ,  Valentina Eberlein  17 ,  Leila Issmail  18 ,  Thomas Grunwald  19 ,  Benjamin Hietel  20 ,  Holger Cynis  21 ,  Jan Münch  22 ,  Konstantin M J Sparrer  23 ,  Armin Ensser  24 ,  Matthias Tenbusch  25 ,  Thomas Dobner  26 ,  Daniel Vitt  27 ,  Hella Kohlhof  28 ,  Friedrich Hahn  29
Affiliations
  • 1. Immunic AG, Gräfelfing, Germany. Electronic address: [email protected].
  • 2. Immunic AG, Gräfelfing, Germany. Electronic address: [email protected].
  • 3. Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: [email protected].
  • 4. Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: [email protected].
  • 5. Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: [email protected].
  • 6. Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: [email protected].
  • 7. Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: [email protected].
  • 8. Leibniz Institute of Virology, Hamburg, Germany. Electronic address: [email protected].
  • 9. Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany. Electronic address: [email protected].
  • 10. Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany. Electronic address: [email protected].
  • 11. Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany. Electronic address: [email protected].
  • 12. Ruhr-University Bochum, Department of Molecular and Medical Virology, Bochum, Germany. Electronic address: [email protected].
  • 13. Leibniz Institute of Virology, Hamburg, Germany; Ruhr-University Bochum, Department of Molecular and Medical Virology, Bochum, Germany; University of Luebeck, Department of Natural Sciences, Institute of Virology and Cell Biology, Lübeck, Germany. Electronic address: [email protected].
  • 14. University Hospital Essen - Ruhrlandklinik, Department of Pulmonary Medicine, Experimental Pneumology, Essen, Germany. Electronic address: [email protected].
  • 15. Institute for Animal Pathology, Freie Universität Berlin, Berlin, Germany. Electronic address: [email protected].
  • 16. Fraunhofer Institute for Cell Therapy and Immunology, Preclinical Validation, Leipzig, Germany. Electronic address: [email protected].
  • 17. Fraunhofer Institute for Cell Therapy and Immunology, Preclinical Validation, Leipzig, Germany. Electronic address: [email protected].
  • 18. Fraunhofer Institute for Cell Therapy and Immunology, Preclinical Validation, Leipzig, Germany. Electronic address: [email protected].
  • 19. Fraunhofer Institute for Cell Therapy and Immunology, Preclinical Validation, Leipzig, Germany. Electronic address: [email protected].
  • 20. Fraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, Halle, Germany. Electronic address: [email protected].
  • 21. Fraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, Halle, Germany; Junior Research Group "Immunomodulation in Pathophysiological Processes", Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany. Electronic address: [email protected].
  • 22. Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany. Electronic address: [email protected].
  • 23. Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany. Electronic address: [email protected].
  • 24. Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: [email protected].
  • 25. Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: [email protected].
  • 26. Leibniz Institute of Virology, Hamburg, Germany. Electronic address: [email protected].
  • 27. Immunic AG, Gräfelfing, Germany. Electronic address: [email protected].
  • 28. Immunic AG, Gräfelfing, Germany. Electronic address: [email protected].
  • 29. Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: [email protected].
PMID: 39306285 DOI: 10.1016/j.antiviral.2024.106008
Abstract

Host-directed antivirals (HDAs) represent an attractive treatment option and a strategy for pandemic preparedness, especially due to their potential broad-spectrum Antiviral activity and high barrier to resistance development. Particularly, dual-targeting HDAs offer a promising approach for Antiviral therapy by simultaneously disrupting multiple pathways essential for viral replication. Izumerogant (IMU-935) targets two host proteins, (i) the retinoic acid receptor-related Orphan Receptor γ isoform 1 (RORγ1), which modulates cellular Cholesterol metabolism, and (ii) the enzyme Dihydroorotate Dehydrogenase (DHODH), which is involved in de novo pyrimidine synthesis. Here, we synthesized optimized derivatives of izumerogant and characterized their Antiviral activity in comparison to a recently described structurally distinct RORγ/DHODH dual inhibitor. Cell culture-based Infection models for enveloped and non-enveloped DNA and RNA viruses, as well as a retrovirus, demonstrated high potency and broad-spectrum activity against human viral pathogens for RORγ/DHODH dual inhibitors at nanomolar concentrations. Comparative analyses with equipotent single-target inhibitors in metabolite supplementation approaches revealed that the dual-targeting mode represents the mechanistic basis for the potent Antiviral activity. For SARS-CoV-2, an optimized dual inhibitor completely blocked viral replication in human airway epithelial cells at 5 nM and displayed a synergistic drug interaction with the nucleoside analog molnupiravir. In a SARS-CoV-2 mouse model, treatment with a dual inhibitor alone, or in combination with molnupiravir, reduced the viral load by 7- and 58-fold, respectively. Considering the clinical safety, oral bioavailability, and tolerability of izumerogant in a recent Phase I study, izumerogant-like drugs represent potent dual-targeting Antiviral HDAs with pronounced broad-spectrum activity for further clinical development.

Keywords
Broad-spectrum antiviral; DHODH inhibitor; Dual-targeting small molecules; Host-targeting antiviral; Human viruses; RORγ inhibitor.
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