Lara Prilop
PC29 – Lara Prilop
University of Hamburg, Germany
lara.prilop@uni-hamburg.de
| Combining DHODH inhibitors and pronucleotides to block viral replication |
| Lara Prilop1, Allison Groseth2, Thomas Hoenen2, and Chris Meier1 1 Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany; 2 Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Südufer 10, D-17493 Greifswald-Insel Riems, Germany; |
| Abstract Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme involved in the de novo pyrimidine synthesis, leading to the formation of uridine monophosphate (UMP). UMP is further converted to other pyrimidine nucleotides needed for the biosynthesis of RNA and DNA. Blocking DHODH with small synthetic molecules should result in a depletion of pyrimidines in the nucleotide pool.[1] In combination therapy, DHODH inhibitors can enhance the effectiveness of viral RNA-polymerase targeting nucleoside analogs by reducing the competition with cellular pyrimidine nucleotides for their incorporation into the viral RNA.[2] For antiviral activity, these compounds must be converted into their triphosphate form, which serves as the final metabolite that inhibits the viral polymerase. To improve bioavailability and bypass phosphorylation steps, prodrug strategies have been developed by our research group[3]. Herein, we describe structural optimizations of the lead structure of a DHODH inhibitor, focusing on improving membrane permeability while maintaining antiviral efficacy. Additionally, the synthesis of 4’-fluorouridine, an antiviral pyrimidine nucleoside analog, and its conversion into a pronucleotide using the TriPPPro approach will be described. |
| References [1] Das, P.; Deng, X. et al. SAR-Based Optimization of a 4-Quinoline Carboxylic Acid Analogue with Potent Antiviral Activity. ACS Med. Chem. Lett. 2013, 4, 517–521 (doi: 10.1021/ml300464h). [2] Luganini, A.; Boschi, D. et al. DHODH inhibitors: What will it take to get them into the clinic as antivirals?, Antiviral Research 2025, 236, 106099 (doi: https://doi.org/10.1016/j.antiviral.2025.106099). [3] Jia, X.; Schols, D.; Meier, C. Lipophilic Triphosphate Prodrugs of Various Nucleoside Analogues. J. Med. Chem. 2020, 63, 6991-7007 (doi: https://doi.org/10.1021/acs.jmedchem.0c00358). |