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

Hahn F, Wangen C, Häge S, Peter AS, Dobler G, Hurst B, Julander J, Fuchs J, Ruzsics Z, Überla K, Jäck HM, Ptak R, Muehler A, Gröppel M, Vitt D, Peelen E, Kohlhof H, Marschall M (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Viruses MDPI

Book Volume: 12

Journal Issue: 12

DOI: 10.3390/v12121394

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.

Authors with CRIS profile

Friedrich Hahn Professur für Virologie Sigrun Häge Institute of Clinical and Molecular Virology Klaus Überla Lehrstuhl für Klinische und Molekulare Virologie Hans-Martin Jäck Professur für Immunologie Manfred Marschall Lehrstuhl für Klinische und Molekulare Virologie

Involved external institutions

Universitätsklinikum Freiburg DE Germany (DE) Utah State University US United States (USA) (US)

How to cite

APA:

Hahn, F., Wangen, C., Häge, S., Peter, A.S., Dobler, G., Hurst, B.,... Marschall, M. (2020). 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, 12(12). https://doi.org/10.3390/v12121394

MLA:

Hahn, Friedrich, et al. "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 12.12 (2020).

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