Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro

Mammarenaviruses cause chronic infections in rodents, which are their predominant natural hosts. Human infection with some of these viruses causes high-consequence disease, posing significant issues in public health. Currently, no FDA-licensed mammarenavirus vaccines are available, and anti-mammaren...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Yu-Jin Kim [verfasserIn] Beatrice Cubitt [verfasserIn] Yingyun Cai [verfasserIn] Jens H. Kuhn [verfasserIn] Daniel Vitt [verfasserIn] Hella Kohlhof [verfasserIn] Juan C. de la Torre [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Schlagwörter:	mammarenavirus DHODH pyrimidine biosynthesis interferon antiviral

Übergeordnetes Werk:	In: Viruses - MDPI AG, 2009, 12(2020), 8, p 821
Übergeordnetes Werk:	volume:12 ; year:2020 ; number:8, p 821

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/v12080821

Katalog-ID:	DOAJ07405127X

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spelling	10.3390/v12080821 doi (DE-627)DOAJ07405127X (DE-599)DOAJ22a4df7bf5db418482a939e8c482b137 DE-627 ger DE-627 rakwb eng QR1-502 Yu-Jin Kim verfasserin aut Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Mammarenaviruses cause chronic infections in rodents, which are their predominant natural hosts. Human infection with some of these viruses causes high-consequence disease, posing significant issues in public health. Currently, no FDA-licensed mammarenavirus vaccines are available, and anti-mammarenavirus drugs are limited to an off-label use of ribavirin, which is only partially efficacious and associated with severe side effects. Dihydroorotate dehydrogenase (DHODH) inhibitors, which block <i<de novo</i< pyrimidine biosynthesis, have antiviral activity against viruses from different families, including <i<Arenaviridae</i<, the taxonomic home of mammarenaviruses. Here, we evaluate five novel DHODH inhibitors for their antiviral activity against mammarenaviruses. All tested DHODH inhibitors were potently active against lymphocytic choriomeningitis virus (LCMV) (half-maximal effective concentrations [EC<sub<50</sub<] in the low nanomolar range, selectivity index [SI] < 1000). The tested DHODH inhibitors did not affect virion cell entry or budding, but rather interfered with viral RNA synthesis. This interference resulted in a potent interferon-independent inhibition of mammarenavirus multiplication in vitro, including the highly virulent Lassa and Junín viruses. mammarenavirus DHODH pyrimidine biosynthesis interferon antiviral Microbiology Beatrice Cubitt verfasserin aut Yingyun Cai verfasserin aut Jens H. Kuhn verfasserin aut Daniel Vitt verfasserin aut Hella Kohlhof verfasserin aut Juan C. de la Torre verfasserin aut In Viruses MDPI AG, 2009 12(2020), 8, p 821 (DE-627)609775871 (DE-600)2516098-9 19994915 nnns volume:12 year:2020 number:8, p 821 https://doi.org/10.3390/v12080821 kostenfrei https://doaj.org/article/22a4df7bf5db418482a939e8c482b137 kostenfrei https://www.mdpi.com/1999-4915/12/8/821 kostenfrei https://doaj.org/toc/1999-4915 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 8, p 821
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allfieldsGer	10.3390/v12080821 doi (DE-627)DOAJ07405127X (DE-599)DOAJ22a4df7bf5db418482a939e8c482b137 DE-627 ger DE-627 rakwb eng QR1-502 Yu-Jin Kim verfasserin aut Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Mammarenaviruses cause chronic infections in rodents, which are their predominant natural hosts. Human infection with some of these viruses causes high-consequence disease, posing significant issues in public health. Currently, no FDA-licensed mammarenavirus vaccines are available, and anti-mammarenavirus drugs are limited to an off-label use of ribavirin, which is only partially efficacious and associated with severe side effects. Dihydroorotate dehydrogenase (DHODH) inhibitors, which block <i<de novo</i< pyrimidine biosynthesis, have antiviral activity against viruses from different families, including <i<Arenaviridae</i<, the taxonomic home of mammarenaviruses. Here, we evaluate five novel DHODH inhibitors for their antiviral activity against mammarenaviruses. All tested DHODH inhibitors were potently active against lymphocytic choriomeningitis virus (LCMV) (half-maximal effective concentrations [EC<sub<50</sub<] in the low nanomolar range, selectivity index [SI] < 1000). The tested DHODH inhibitors did not affect virion cell entry or budding, but rather interfered with viral RNA synthesis. This interference resulted in a potent interferon-independent inhibition of mammarenavirus multiplication in vitro, including the highly virulent Lassa and Junín viruses. mammarenavirus DHODH pyrimidine biosynthesis interferon antiviral Microbiology Beatrice Cubitt verfasserin aut Yingyun Cai verfasserin aut Jens H. Kuhn verfasserin aut Daniel Vitt verfasserin aut Hella Kohlhof verfasserin aut Juan C. de la Torre verfasserin aut In Viruses MDPI AG, 2009 12(2020), 8, p 821 (DE-627)609775871 (DE-600)2516098-9 19994915 nnns volume:12 year:2020 number:8, p 821 https://doi.org/10.3390/v12080821 kostenfrei https://doaj.org/article/22a4df7bf5db418482a939e8c482b137 kostenfrei https://www.mdpi.com/1999-4915/12/8/821 kostenfrei https://doaj.org/toc/1999-4915 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 8, p 821
allfieldsSound	10.3390/v12080821 doi (DE-627)DOAJ07405127X (DE-599)DOAJ22a4df7bf5db418482a939e8c482b137 DE-627 ger DE-627 rakwb eng QR1-502 Yu-Jin Kim verfasserin aut Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Mammarenaviruses cause chronic infections in rodents, which are their predominant natural hosts. Human infection with some of these viruses causes high-consequence disease, posing significant issues in public health. Currently, no FDA-licensed mammarenavirus vaccines are available, and anti-mammarenavirus drugs are limited to an off-label use of ribavirin, which is only partially efficacious and associated with severe side effects. Dihydroorotate dehydrogenase (DHODH) inhibitors, which block <i<de novo</i< pyrimidine biosynthesis, have antiviral activity against viruses from different families, including <i<Arenaviridae</i<, the taxonomic home of mammarenaviruses. Here, we evaluate five novel DHODH inhibitors for their antiviral activity against mammarenaviruses. All tested DHODH inhibitors were potently active against lymphocytic choriomeningitis virus (LCMV) (half-maximal effective concentrations [EC<sub<50</sub<] in the low nanomolar range, selectivity index [SI] < 1000). The tested DHODH inhibitors did not affect virion cell entry or budding, but rather interfered with viral RNA synthesis. This interference resulted in a potent interferon-independent inhibition of mammarenavirus multiplication in vitro, including the highly virulent Lassa and Junín viruses. mammarenavirus DHODH pyrimidine biosynthesis interferon antiviral Microbiology Beatrice Cubitt verfasserin aut Yingyun Cai verfasserin aut Jens H. Kuhn verfasserin aut Daniel Vitt verfasserin aut Hella Kohlhof verfasserin aut Juan C. de la Torre verfasserin aut In Viruses MDPI AG, 2009 12(2020), 8, p 821 (DE-627)609775871 (DE-600)2516098-9 19994915 nnns volume:12 year:2020 number:8, p 821 https://doi.org/10.3390/v12080821 kostenfrei https://doaj.org/article/22a4df7bf5db418482a939e8c482b137 kostenfrei https://www.mdpi.com/1999-4915/12/8/821 kostenfrei https://doaj.org/toc/1999-4915 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 8, p 821
language	English
source	In Viruses 12(2020), 8, p 821 volume:12 year:2020 number:8, p 821
sourceStr	In Viruses 12(2020), 8, p 821 volume:12 year:2020 number:8, p 821
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institution	findex.gbv.de
topic_facet	mammarenavirus DHODH pyrimidine biosynthesis interferon antiviral Microbiology
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container_title	Viruses
authorswithroles_txt_mv	Yu-Jin Kim @@aut@@ Beatrice Cubitt @@aut@@ Yingyun Cai @@aut@@ Jens H. Kuhn @@aut@@ Daniel Vitt @@aut@@ Hella Kohlhof @@aut@@ Juan C. de la Torre @@aut@@
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callnumber-first	Q - Science
author	Yu-Jin Kim
spellingShingle	Yu-Jin Kim misc QR1-502 misc mammarenavirus misc DHODH misc pyrimidine biosynthesis misc interferon misc antiviral misc Microbiology Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro
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topic_title	QR1-502 Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro mammarenavirus DHODH pyrimidine biosynthesis interferon antiviral
topic	misc QR1-502 misc mammarenavirus misc DHODH misc pyrimidine biosynthesis misc interferon misc antiviral misc Microbiology
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title	Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro
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title_full	Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro
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title_sort	novel dihydroorotate dehydrogenase inhibitors with potent interferon-independent antiviral activity against mammarenaviruses in vitro
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title_auth	Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro
abstract	Mammarenaviruses cause chronic infections in rodents, which are their predominant natural hosts. Human infection with some of these viruses causes high-consequence disease, posing significant issues in public health. Currently, no FDA-licensed mammarenavirus vaccines are available, and anti-mammarenavirus drugs are limited to an off-label use of ribavirin, which is only partially efficacious and associated with severe side effects. Dihydroorotate dehydrogenase (DHODH) inhibitors, which block <i<de novo</i< pyrimidine biosynthesis, have antiviral activity against viruses from different families, including <i<Arenaviridae</i<, the taxonomic home of mammarenaviruses. Here, we evaluate five novel DHODH inhibitors for their antiviral activity against mammarenaviruses. All tested DHODH inhibitors were potently active against lymphocytic choriomeningitis virus (LCMV) (half-maximal effective concentrations [EC<sub<50</sub<] in the low nanomolar range, selectivity index [SI] < 1000). The tested DHODH inhibitors did not affect virion cell entry or budding, but rather interfered with viral RNA synthesis. This interference resulted in a potent interferon-independent inhibition of mammarenavirus multiplication in vitro, including the highly virulent Lassa and Junín viruses.
abstractGer	Mammarenaviruses cause chronic infections in rodents, which are their predominant natural hosts. Human infection with some of these viruses causes high-consequence disease, posing significant issues in public health. Currently, no FDA-licensed mammarenavirus vaccines are available, and anti-mammarenavirus drugs are limited to an off-label use of ribavirin, which is only partially efficacious and associated with severe side effects. Dihydroorotate dehydrogenase (DHODH) inhibitors, which block <i<de novo</i< pyrimidine biosynthesis, have antiviral activity against viruses from different families, including <i<Arenaviridae</i<, the taxonomic home of mammarenaviruses. Here, we evaluate five novel DHODH inhibitors for their antiviral activity against mammarenaviruses. All tested DHODH inhibitors were potently active against lymphocytic choriomeningitis virus (LCMV) (half-maximal effective concentrations [EC<sub<50</sub<] in the low nanomolar range, selectivity index [SI] < 1000). The tested DHODH inhibitors did not affect virion cell entry or budding, but rather interfered with viral RNA synthesis. This interference resulted in a potent interferon-independent inhibition of mammarenavirus multiplication in vitro, including the highly virulent Lassa and Junín viruses.
abstract_unstemmed	Mammarenaviruses cause chronic infections in rodents, which are their predominant natural hosts. Human infection with some of these viruses causes high-consequence disease, posing significant issues in public health. Currently, no FDA-licensed mammarenavirus vaccines are available, and anti-mammarenavirus drugs are limited to an off-label use of ribavirin, which is only partially efficacious and associated with severe side effects. Dihydroorotate dehydrogenase (DHODH) inhibitors, which block <i<de novo</i< pyrimidine biosynthesis, have antiviral activity against viruses from different families, including <i<Arenaviridae</i<, the taxonomic home of mammarenaviruses. Here, we evaluate five novel DHODH inhibitors for their antiviral activity against mammarenaviruses. All tested DHODH inhibitors were potently active against lymphocytic choriomeningitis virus (LCMV) (half-maximal effective concentrations [EC<sub<50</sub<] in the low nanomolar range, selectivity index [SI] < 1000). The tested DHODH inhibitors did not affect virion cell entry or budding, but rather interfered with viral RNA synthesis. This interference resulted in a potent interferon-independent inhibition of mammarenavirus multiplication in vitro, including the highly virulent Lassa and Junín viruses.
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title_short	Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro
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up_date	2024-07-03T21:04:17.538Z
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Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro

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