Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 14; pp. 5777 - 5782
• Main Authors: Hoffmann, Hans-Heinrich, Kunz, Andrea, Simon, Viviana A, Palese, Peter, Shaw, Megan L
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.04.2011; National Acad Sciences
• Subjects: Animals; Antiviral Agents - pharmacology; antiviral properties; Antivirals; Autoradiography; Avian orthoavulavirus 1; beta-Galactosidase - metabolism; Biological Sciences; Biosynthesis; Carbamates; Cell Line, Tumor; Cell lines; Cell Survival - drug effects; Cells; Chickens; Dengue virus; Deoxyribonucleic acid; DNA; DNA Primers - genetics; Epithelial cells; Hepatitis C virus; Human adenovirus; Human immunodeficiency virus; Humans; Indoles - pharmacology; Influenza virus; Inhibitory concentration 50; Lamivudine; Mammals; Nevirapine; Newcastle disease; Newcastle disease virus; orotic acid; Orthomyxoviridae; Oxadiazoles - pharmacology; Oxidoreductases Acting on CH-CH Group Donors - metabolism; Proteins; Pyrimidines; Pyrimidines - biosynthesis; Pyrimidines - metabolism; Pyrrolidinones; Raltegravir Potassium; Retrovirus; Ribonucleic acid; RNA; Sindbis virus; Species Specificity; Sulfonamides; Time Factors; uracil; Vaccinia virus; Vector-borne diseases; Vero cells; vertebrate viruses; Vesicular stomatitis virus; Vesiculovirus; virus replication; Virus Replication - drug effects; Viruses; Viruses - drug effects; Viruses - growth & development; West Nile virus
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1101143108

Compound A3 was identified in a high-throughput screen for inhibitors of influenza virus replication. It displays broad-spectrum antiviral activity, and at noncytotoxic concentrations it is shown to inhibit the replication of negative-sense RNA viruses (influenza viruses A and B, Newcastle disease virus, and vesicular stomatitis virus), positive-sense RNA viruses (Sindbis virus, hepatitis C virus, West Nile virus, and dengue virus), DNA viruses (vaccinia virus and human adenovirus), and retroviruses (HIV). In contrast to mammalian cells, inhibition of viral replication by A3 is absent in chicken cells, which suggests species-specific activity of A3. Correspondingly, the antiviral activity of A3 can be linked to a cellular protein, dihydroorotate dehydrogenase (DHODH), which is an enzyme in the de novo pyrimidine biosynthesis pathway. Viral replication of both RNA and DNA viruses can be restored in the presence of excess uracil, which promotes pyrimidine salvage, or excess orotic acid, which is the product of DHODH in the de novo pyrimidine biosynthesis pathway. Based on these findings, it is proposed that A3 acts by depleting pyrimidine pools, which are crucial for efficient virus replication.