2. Academic Validation
  3. Orally bioavailable RORγ/DHODH dual host-targeting small molecules with broad-spectrum antiviral activity

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

Affiliations

  • 1 Immunic AG, Gräfelfing, Germany. Electronic address: alexandra.herrmann@imux.com.
  • 2 Immunic AG, Gräfelfing, Germany. Electronic address: christian.gege@imux.com.
  • 3 Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: christina.wangen@uk-erlangen.de.
  • 4 Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: sabrina.wagner@uk-erlangen.de.
  • 5 Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: melanie.koegler@uk-erlangen.de.
  • 6 Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: arne.cordsmeier@uk-erlangen.de.
  • 7 Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: pascal.irrgang@uk-erlangen.de.
  • 8 Leibniz Institute of Virology, Hamburg, Germany. Electronic address: winghang.ip@leibniz-liv.de.
  • 9 Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany. Electronic address: tatjanaweil@yahoo.de.
  • 10 Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany. Electronic address: victoria.hunszinger@uni-ulm.de.
  • 11 Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany. Electronic address: ruediger.gross@uni-ulm.de.
  • 12 Ruhr-University Bochum, Department of Molecular and Medical Virology, Bochum, Germany. Electronic address: natalie.heinen@ruhr-uni-bochum.de.
  • 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: stephanie.pfaender@leibniz-liv.de.
  • 14 University Hospital Essen - Ruhrlandklinik, Department of Pulmonary Medicine, Experimental Pneumology, Essen, Germany. Electronic address: sebastian.reuter@rlk.uk-essen.de.
  • 15 Institute for Animal Pathology, Freie Universität Berlin, Berlin, Germany. Electronic address: robert.klopfleisch@fu-berlin.de.
  • 16 Fraunhofer Institute for Cell Therapy and Immunology, Preclinical Validation, Leipzig, Germany. Electronic address: nadja.uhlig@izi.fraunhofer.de.
  • 17 Fraunhofer Institute for Cell Therapy and Immunology, Preclinical Validation, Leipzig, Germany. Electronic address: valentina.eberlein@izi.fraunhofer.de.
  • 18 Fraunhofer Institute for Cell Therapy and Immunology, Preclinical Validation, Leipzig, Germany. Electronic address: leila.issmail@izi.fraunhofer.de.
  • 19 Fraunhofer Institute for Cell Therapy and Immunology, Preclinical Validation, Leipzig, Germany. Electronic address: thomas.grunwald@izi.fraunhofer.de.
  • 20 Fraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, Halle, Germany. Electronic address: benjamin.hietel@izi.fraunhofer.de.
  • 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: holger.cynis@izi.fraunhofer.de.
  • 22 Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany. Electronic address: jan.muench@uni-ulm.de.
  • 23 Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany. Electronic address: konstantin.sparrer@uni-ulm.de.
  • 24 Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: armin.ensser@fau.de.
  • 25 Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: matthias.tenbusch@fau.de.
  • 26 Leibniz Institute of Virology, Hamburg, Germany. Electronic address: thomas.dobner@leibniz-liv.de.
  • 27 Immunic AG, Gräfelfing, Germany. Electronic address: daniel.vitt@imux.com.
  • 28 Immunic AG, Gräfelfing, Germany. Electronic address: hella.kohlhof@imux.com.
  • 29 Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: friedrich.hahn@uk-erlangen.de.
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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