Journal Article

DZNE-2026-00687

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png DHODH Inhibitors Based on the Vidofludimus Scaffold Containing Carboxylic Acid Bioisosteres Exert a Superior Broad-Spectrum Antiviral Activity.

Herrmann, A.Extern* ; Hahn, F. ; Wangen, C. ; Wagner, S. ; Cordsmeier, A. ; Irrgang, P. ; Weil, T. ; Hunszinger, V.Extern* ; 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, K. M. J.DZNE* ; Marschall, M. ; Kohlhof, H. ; Vitt, D. ; Gege, C.

2026
ACS Washington, DC

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Please use a persistent id in citations: 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.

Keyword(s): Antiviral Agents: pharmacology (MeSH) ; Antiviral Agents: chemistry (MeSH) ; Antiviral Agents: chemical synthesis (MeSH) ; Antiviral Agents: metabolism (MeSH) ; Dihydroorotate Dehydrogenase: antagonists & inhibitors (MeSH) ; Humans (MeSH) ; Oxidoreductases Acting on CH-CH Group Donors: antagonists & inhibitors (MeSH) ; Oxidoreductases Acting on CH-CH Group Donors: metabolism (MeSH) ; Animals (MeSH) ; Bioisosterism (MeSH) ; Carboxylic Acids: chemistry (MeSH) ; Carboxylic Acids: pharmacology (MeSH) ; SARS-CoV-2: drug effects (MeSH) ; Enzyme Inhibitors: pharmacology (MeSH) ; Enzyme Inhibitors: chemistry (MeSH) ; Enzyme Inhibitors: chemical synthesis (MeSH) ; Structure-Activity Relationship (MeSH) ; RNA Viruses: drug effects (MeSH) ; DNA Viruses: drug effects (MeSH) ; Antiviral Agents ; Dihydroorotate Dehydrogenase ; Oxidoreductases Acting on CH-CH Group Donors ; Carboxylic Acids ; Enzyme Inhibitors

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Contributing Institute(s):

1. Neurovirology and Neuroinflammation (AG Sparrer)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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