IMU-838, a developmental DHODH inhibitor in phase II for autoimmune disease, shows anti-SARS-CoV-2 and broad-spectrum antiviral efficacy in vitro

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

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• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Viruses. - 12, 12 (2020) , 1394, ISSN: 1999-4915

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2020
• Urheber: Hahn, Friedrich ; Wangen, Christina ; Häge, Sigrun ; Peter, Antonia Sophia ; Dobler, Gerhard ; Hurst, Brett ; Julander, Justin ; Fuchs, Jonas ; Ruzsics, Zsolt ; Überla, Klaus Thomas ; Jäck, Hans-Martin ; Ptak, Roger ; Muehler, Andreas ; Gröppel, Manfred ; Vitt, Daniel ; Peelen, Evelyn ; Kohlhof, Hella ; Marschall, Manfred

Weitere Informationen

• DOI: 10.3390/v12121394
• URN: urn:nbn:de:bsz:25-freidok-1745009
• Rechteinformation: Der Zugriff auf das Objekt ist unbeschränkt möglich.