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

[tetano]

Viruses


. 2020 Dec 5;12(12):E1394.
doi: 10.3390/v12121394.
IMU-838, a Developmental DHODH Inhibitor in Phase II for Autoimmune Disease, Shows Anti-SARS-CoV-2 and Broad-Spectrum Antiviral Efficacy In Vitro


Friedrich Hahn ¹ , Christina Wangen ¹ , Sigrun H?ge ¹ , Antonia Sophia Peter ¹ , Gerhard Dobler ² , Brett Hurst ³ , Justin Julander ³ , Jonas Fuchs ⁴ , Zsolt Ruzsics ⁴ , Klaus ?berla ¹ , Hans-Martin J?ck ⁵ , Roger Ptak ⁶ , Andreas Muehler ⁷ , Manfred Gr?ppel ⁷ , Daniel Vitt ⁷ , Evelyn Peelen ⁷ , Hella Kohlhof ⁷ , Manfred Marschall ¹



Affiliations

• PMID: 33291455
• 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, EC_50, of 7.6 ? 5.8 ?M); (iii) anti-SARS-CoV-2 activity was distinct from cytotoxic effects (half-cytotoxic concentration, CC_50, >100 ?M); (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.