1. Academic Validation
  2. IMU-838, a Developmental DHODH Inhibitor in Phase II for Autoimmune Disease, Shows Anti-SARS-CoV-2 and Broad-Spectrum Antiviral Efficacy In Vitro

IMU-838, a Developmental DHODH Inhibitor in Phase II for Autoimmune Disease, Shows Anti-SARS-CoV-2 and Broad-Spectrum Antiviral Efficacy In Vitro

  • Viruses. 2020 Dec 5;12(12):1394. doi: 10.3390/v12121394.
Friedrich Hahn 1 Christina Wangen 1 Sigrun Häge 1 Antonia Sophia Peter 1 Gerhard Dobler 2 Brett Hurst 3 Justin Julander 3 Jonas Fuchs 4 Zsolt Ruzsics 4 Klaus Überla 1 Hans-Martin Jäck 5 Roger Ptak 6 Andreas Muehler 7 Manfred Gröppel 7 Daniel Vitt 7 Evelyn Peelen 7 Hella Kohlhof 7 Manfred Marschall 1
Affiliations

Affiliations

  • 1 Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Schlossgarten 4, 91054 Erlangen, Germany.
  • 2 Institute of Microbiology, Bundeswehr, Neuherbergstraße 11, 80937 München, Germany.
  • 3 Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322, USA.
  • 4 Institute for Virology, University Medical Center/Universitätsklinikum Freiburg, Hermann-Herder Str 11, 79104 Freiburg, Germany.
  • 5 Division of Immunology, Department of Medicine 3, FAU, Glückstraße 6, 91054 Erlangen, Germany.
  • 6 Drug Development Division, Infectious Disease Research, Southern Research, 431 Aviation Way, Frederick, MD 21701, USA.
  • 7 Immunic AG, Lochhamer Schlag 21, 82166 Gräfelfing, Germany.
Abstract

The ongoing pandemic spread of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) demands skillful strategies for novel drug development, drug repurposing and cotreatments, in particular focusing on existing candidates of host-directed antivirals (HDAs). The developmental drug IMU-838, currently being investigated in a phase 2b trial in patients suffering from autoimmune diseases, represents an inhibitor of human Dihydroorotate Dehydrogenase (DHODH) with a recently proven Antiviral activity in vitro and in vivo. Here, we established an analysis system for assessing the Antiviral potency of IMU-838 and DHODH-directed back-up drugs in cultured cell-based Infection models. By the use of SARS-CoV-2-specific immunofluorescence, Western blot, in-cell ELISA, viral yield reduction and RT-qPCR methods, we demonstrated the following: (i) IMU-838 and back-ups show anti-SARS-CoV-2 activity at several levels of viral replication, i.e., protein production, double-strand RNA synthesis, and release of infectious virus; (ii) Antiviral efficacy in Vero cells was demonstrated in a micromolar range (IMU-838 half-maximal effective concentration, EC50, of 7.6 ± 5.8 µM); (iii) anti-SARS-CoV-2 activity was distinct from cytotoxic effects (half-cytotoxic concentration, CC50, >100 µM); (iv) the drug in vitro potency was confirmed using several Vero lineages and human cells; (v) combination with remdesivir showed enhanced anti-SARS-CoV-2 activity; (vi) vidofludimus, the active determinant of IMU-838, exerted a broad-spectrum activity against a selection of major human pathogenic viruses. These findings strongly suggest that developmental DHODH inhibitors represent promising candidates for use as anti-SARS-CoV-2 therapeutics.

Keywords

IMU-838; SARS-CoV-2; antiviral therapy; dihydroorotate dehydrogenase (DHODH) inhibitors; host-directed antivirals (HDAs); vidofludimus.

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