Synthesis and Characterization of DHODH Inhibitors Based on the Vidofludimus Scaffold with Pronounced Anti-SARS-CoV-2 Activity

Gege C, Hahn F, Wangen C, Häge S, Herrmann A, Uhlig N, Eberlein V, Issmail L, Klopfleisch R, Grunwald T, Marschall M, Kohlhof H, Vitt D (2024)

Publication Language: English

Publication Type: Journal article

Publication year: 2024

Journal

ChemMedChem Wiley

Book Volume: 19

Article Number: e202400292

Journal Issue: 19

DOI: 10.1002/cmdc.202400292

Abstract

New strategies for the rapid development of broad-spectrum antiviral therapies are urgently required for emerging and re-emerging viruses like the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Host-directed antivirals that target universal cellular metabolic pathways necessary for viral replication present a promising approach with broad-spectrum activity and low potential for development of viral resistance. Dihydroorotate dehydrogenase (DHODH) was identified as one of those universal host factors essential for the replication of many clinically relevant human pathogenic viruses. DHODH is the rate-limiting enzyme catalyzing the fourth step in the de novo pyrimidine synthesis. Therefore, it is also developed as a therapeutic target for many diseases relying on cellular pyrimidine resources, such as cancer, autoimmune diseases and viral or bacterial infection. Thus, several DHODH inhibitors, including vidofludimus calcium (VidoCa, IMU-838), are currently in development or have been investigated in clinical trials for the treatment of virus infections such as SARS-CoV-2-mediated coronavirus disease 19 (COVID-19). Here, we report the medicinal chemistry optimization of VidoCa that resulted in metabolically more stable derivatives with improved DHODH target inhibition in various mammalian species, which translated into improved efficacy against SARS-CoV-2.

Authors with CRIS profile

Friedrich Hahn Institute of Clinical and Molecular Virology Sigrun Häge Institute of Clinical and Molecular Virology Manfred Marschall Lehrstuhl für Klinische und Molekulare Virologie

Involved external institutions

Immunic AG DE Germany (DE) Fraunhofer-Institut für Zelltherapie und Immunologie (IZI) DE Germany (DE) Freie Universität Berlin DE Germany (DE)

How to cite

APA:

Gege, C., Hahn, F., Wangen, C., Häge, S., Herrmann, A., Uhlig, N.,... Vitt, D. (2024). Synthesis and Characterization of DHODH Inhibitors Based on the Vidofludimus Scaffold with Pronounced Anti-SARS-CoV-2 Activity. ChemMedChem, 19(19). https://doi.org/10.1002/cmdc.202400292

MLA:

Gege, Christian, et al. "Synthesis and Characterization of DHODH Inhibitors Based on the Vidofludimus Scaffold with Pronounced Anti-SARS-CoV-2 Activity." ChemMedChem 19.19 (2024).

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