DHODH Inhibitors Based on the Vidofludimus Scaffold Containing Carboxylic Acid Bioisosteres Exert a Superior Broad-Spectrum Antiviral Activity

Herrmann A, Hahn F, Wangen C, Wagner S, Cordsmeier A, Irrgang P, Weil T, Hunszinger V, Groß R, Heinen N, Pfaender S, Westhoven S, Reuter S, Schedel M, Uhlig N, Eberlein V, Issmail L, Grunwald T, Klopfleisch R, Enßer A, Tenbusch M, Münch J, Sparrer KM, Marschall M, Kohlhof H, Vitt D, Gege C (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 69

Pages Range: 14255-14274

Journal Issue: 12

DOI: 10.1021/acs.jmedchem.5c03715

Abstract

Emerging and re-emerging viral infections demand the rapid development of broad-spectrum antivirals. Host-directed therapies targeting cellular metabolic pathways required for viral replication offer a promising strategy with a low risk of resistance. Dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in de novo pyrimidine synthesis, is essential for the replication of many human pathogenic viruses. Several DHODH inhibitors, including vidofludimus calcium, are under clinical investigation for viral diseases, such as coronavirus disease 19 (COVID-19). We report medicinal chemistry optimization of vidofludimus, yielding more potent derivatives with improved DHODH inhibition across mammalian species and enhanced activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Optimized compounds also showed broad-spectrum antiviral activity against enveloped and nonenveloped DNA and RNA viruses and a retrovirus, with single-digit nanomolar potency and no detectable cytotoxicity. Selectivity indices exceeded 50,000, highlighting the therapeutic potential of this target. These findings identify this compound class as a promising starting point for host-directed antivirals (HDAs), as well as for pandemic preparedness and applications in other disease areas.

Authors with CRIS profile

Involved external institutions

Immunic AG Germany (DE) Universitätsklinikum Ulm Germany (DE) Fraunhofer-Institut für Zelltherapie und Immunologie (IZI) Germany (DE) Ruhr-Universität Bochum (RUB) Germany (DE) Universität zu Lübeck Germany (DE) Heinrich-Pette-Institut (HPI), Leibniz-Institut für Experimentelle Virologie / Heinrich Pette Institute – Leibniz Institute for Experimental Virology Germany (DE) Universitätsklinikum Essen Germany (DE) Freie Universität Berlin Germany (DE)

How to cite

APA:

Herrmann, A., Hahn, F., Wangen, C., Wagner, S., Cordsmeier, A., Irrgang, P.,... Gege, C. (2026). DHODH Inhibitors Based on the Vidofludimus Scaffold Containing Carboxylic Acid Bioisosteres Exert a Superior Broad-Spectrum Antiviral Activity. Journal of Medicinal Chemistry, 69(12), 14255-14274. https://doi.org/10.1021/acs.jmedchem.5c03715

MLA:

Herrmann, Alexandra, et al. "DHODH Inhibitors Based on the Vidofludimus Scaffold Containing Carboxylic Acid Bioisosteres Exert a Superior Broad-Spectrum Antiviral Activity." Journal of Medicinal Chemistry 69.12 (2026): 14255-14274.

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