Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis
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 v...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 14; pp. 5777 - 5782 |
|---|---|
| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
05.04.2011
National Acad Sciences |
| Subjects | |
| Online Access | Get full text |
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| Abstract | 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. |
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| AbstractList | 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. 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.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. 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. [PUBLICATION ABSTRACT] |
| Author | Hoffmann, Hans-Heinrich Kunz, Andrea Palese, Peter Simon, Viviana A Shaw, Megan L |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/21436031$$D View this record in MEDLINE/PubMed |
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| Notes | http://dx.doi.org/10.1073/pnas.1101143108 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 Edited by Thomas E. Shenk, Princeton University, Princeton, NJ, and approved February 25, 2011 (received for review February 4, 2011) Author contributions: H.-H.H., P.P., and M.L.S. designed research; H.-H.H. and A.K. performed research; A.K. and V.A.S. contributed new reagents/analytic tools; H.-H.H., A.K., V.A.S., P.P., and M.L.S. analyzed data; and H.-H.H., V.A.S., and M.L.S. wrote the paper. 1Present address: Institute of Tropical Medicine and International Health, Charité, University Medicine Berlin, Berlin 14050, Germany. |
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| SubjectTerms | 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 |
| Title | Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis |
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