Giuseppe
Emeritus
Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis (PNAS, abstract, edited)
[Source: Proc Natl Acad Sci USA, full text: <cite cite="http://www.pnas.org/content/108/14/5777.short?rss=1">Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis</cite>. Abstract, edited.]
Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis
1. Hans-Heinrich Hoffmann a, 2. Andrea Kunz a,b,1, 3. Viviana A. Simon a,b,c, 4. Peter Palese a,b,2, and 5. Megan L. Shaw a,2
Author Affiliations
1. a Department of Microbiology,
2. b Department of Medicine, and
3. c Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029
1. Edited by Thomas E. Shenk, Princeton University, Princeton, NJ, and approved February 25, 2011 (received for review February 4, 2011)
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.
Footnotes
* ↵1Present address: Institute of Tropical Medicine and International Health, Charit?, University Medicine Berlin, Berlin 14050, Germany.
* ↵2To whom correspondence may be addressed. E-mail: megan.shaw@mssm.edu or peter.palese@mssm.edu.
* 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.
* Conflict of interest statement: A provisional patent application has been filed by Mount Sinai School of Medicine covering the A3 compound.
* This article is a PNAS Direct Submission.
* This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1101143108/-/DCSupplemental.
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[Source: Proc Natl Acad Sci USA, full text: <cite cite="http://www.pnas.org/content/108/14/5777.short?rss=1">Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis</cite>. Abstract, edited.]
Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis
1. Hans-Heinrich Hoffmann a, 2. Andrea Kunz a,b,1, 3. Viviana A. Simon a,b,c, 4. Peter Palese a,b,2, and 5. Megan L. Shaw a,2
Author Affiliations
1. a Department of Microbiology,
2. b Department of Medicine, and
3. c Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029
1. Edited by Thomas E. Shenk, Princeton University, Princeton, NJ, and approved February 25, 2011 (received for review February 4, 2011)
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.
Footnotes
* ↵1Present address: Institute of Tropical Medicine and International Health, Charit?, University Medicine Berlin, Berlin 14050, Germany.
* ↵2To whom correspondence may be addressed. E-mail: megan.shaw@mssm.edu or peter.palese@mssm.edu.
* 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.
* Conflict of interest statement: A provisional patent application has been filed by Mount Sinai School of Medicine covering the A3 compound.
* This article is a PNAS Direct Submission.
* This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1101143108/-/DCSupplemental.
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