Inhibition of Junin virus RNA synthesis by an antiviral acridone derivative
There are no specific approved drugs for the treatment of agents of viral hemorrhagic fevers (HF) and antiviral therapies against these viruses are urgently needed. The present study characterizes the potent and selective antiviral activity against the HF causing arenavirus Junin virus (JUNV) of the...
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todo:paper_01663542_v93_n1_p16_Sepulveda2023-10-03T15:03:53Z Inhibition of Junin virus RNA synthesis by an antiviral acridone derivative Sepúlveda, C.S. García, C.C. Fascio, M.L. D'Accorso, N.B. Docampo Palacios, M.L. Pellón, R.F. Damonte, E.B. Acridone Antiviral Hemorrhagic fever virus Inosine monophosphate dehydrogenase (IMPDH) Junin virus RNA synthesis 10 allyl 6 chloro 4 methoxy 9(10h)acridone acridone derivative guanosine inosinate dehydrogenase mycophenolic acid ribavirin unclassified drug virus RNA adsorption animal cell antiviral activity article controlled study drug potency hemorrhagic fever infection internalization Junin virus nonhuman priority journal real time polymerase chain reaction RNA synthesis Vero cell virogenesis Acridones Allyl Compounds Animals Antiviral Agents Cercopithecus aethiops Cytopathogenic Effect, Viral Gene Expression Regulation, Viral Guanosine Junin virus Microbial Sensitivity Tests RNA, Viral Vero Cells Virus Replication Arenavirus Junin virus There are no specific approved drugs for the treatment of agents of viral hemorrhagic fevers (HF) and antiviral therapies against these viruses are urgently needed. The present study characterizes the potent and selective antiviral activity against the HF causing arenavirus Junin virus (JUNV) of the compound 10-allyl-6-chloro-4-methoxy-9(10H)-acridone, designated 3f. The effectiveness of 3f to inhibit JUNV multiplication was not importantly affected by the initial multiplicity of infection, with similar effective concentration 50% (EC 50) values in virus yield inhibition assays performed in Vero cells in the range of 0.2-40 plaque forming units (PFU)/cell. Mechanistic studies demonstrated that 3f did not affect the initial steps of adsorption and internalization. The subsequent process of viral RNA synthesis was strongly inhibited, as quantified by real time RT-PCR in compound-treated cells relative to non-treated cells. The addition of exogenous guanosine rescued the infectivity and RNA synthesis of JUNV in 3f-treated cells in a dose-dependent manner, but the reversal was partial, suggesting that the reduction of the GTP pool contributed to the antiviral activity of 3f, but it was not the main operative mechanism. The comparison of 3f with two other viral RNA inhibitors, ribavirin and mycophenolic acid, showed that ribavirin did not act against JUNV through the cellular enzyme inosine monophosphate dehydrogenase (IMPDH) inhibition whereas the anti-JUNV activity of mycophenolic acid was mainly targeted at this enzyme. © 2011 Elsevier B.V. Fil:Sepúlveda, C.S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:García, C.C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Fascio, M.L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:D'Accorso, N.B. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Damonte, E.B. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_01663542_v93_n1_p16_Sepulveda |
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Universidad de Buenos Aires |
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I-28 |
| repository_str |
R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Acridone Antiviral Hemorrhagic fever virus Inosine monophosphate dehydrogenase (IMPDH) Junin virus RNA synthesis 10 allyl 6 chloro 4 methoxy 9(10h)acridone acridone derivative guanosine inosinate dehydrogenase mycophenolic acid ribavirin unclassified drug virus RNA adsorption animal cell antiviral activity article controlled study drug potency hemorrhagic fever infection internalization Junin virus nonhuman priority journal real time polymerase chain reaction RNA synthesis Vero cell virogenesis Acridones Allyl Compounds Animals Antiviral Agents Cercopithecus aethiops Cytopathogenic Effect, Viral Gene Expression Regulation, Viral Guanosine Junin virus Microbial Sensitivity Tests RNA, Viral Vero Cells Virus Replication Arenavirus Junin virus |
| spellingShingle |
Acridone Antiviral Hemorrhagic fever virus Inosine monophosphate dehydrogenase (IMPDH) Junin virus RNA synthesis 10 allyl 6 chloro 4 methoxy 9(10h)acridone acridone derivative guanosine inosinate dehydrogenase mycophenolic acid ribavirin unclassified drug virus RNA adsorption animal cell antiviral activity article controlled study drug potency hemorrhagic fever infection internalization Junin virus nonhuman priority journal real time polymerase chain reaction RNA synthesis Vero cell virogenesis Acridones Allyl Compounds Animals Antiviral Agents Cercopithecus aethiops Cytopathogenic Effect, Viral Gene Expression Regulation, Viral Guanosine Junin virus Microbial Sensitivity Tests RNA, Viral Vero Cells Virus Replication Arenavirus Junin virus Sepúlveda, C.S. García, C.C. Fascio, M.L. D'Accorso, N.B. Docampo Palacios, M.L. Pellón, R.F. Damonte, E.B. Inhibition of Junin virus RNA synthesis by an antiviral acridone derivative |
| topic_facet |
Acridone Antiviral Hemorrhagic fever virus Inosine monophosphate dehydrogenase (IMPDH) Junin virus RNA synthesis 10 allyl 6 chloro 4 methoxy 9(10h)acridone acridone derivative guanosine inosinate dehydrogenase mycophenolic acid ribavirin unclassified drug virus RNA adsorption animal cell antiviral activity article controlled study drug potency hemorrhagic fever infection internalization Junin virus nonhuman priority journal real time polymerase chain reaction RNA synthesis Vero cell virogenesis Acridones Allyl Compounds Animals Antiviral Agents Cercopithecus aethiops Cytopathogenic Effect, Viral Gene Expression Regulation, Viral Guanosine Junin virus Microbial Sensitivity Tests RNA, Viral Vero Cells Virus Replication Arenavirus Junin virus |
| description |
There are no specific approved drugs for the treatment of agents of viral hemorrhagic fevers (HF) and antiviral therapies against these viruses are urgently needed. The present study characterizes the potent and selective antiviral activity against the HF causing arenavirus Junin virus (JUNV) of the compound 10-allyl-6-chloro-4-methoxy-9(10H)-acridone, designated 3f. The effectiveness of 3f to inhibit JUNV multiplication was not importantly affected by the initial multiplicity of infection, with similar effective concentration 50% (EC 50) values in virus yield inhibition assays performed in Vero cells in the range of 0.2-40 plaque forming units (PFU)/cell. Mechanistic studies demonstrated that 3f did not affect the initial steps of adsorption and internalization. The subsequent process of viral RNA synthesis was strongly inhibited, as quantified by real time RT-PCR in compound-treated cells relative to non-treated cells. The addition of exogenous guanosine rescued the infectivity and RNA synthesis of JUNV in 3f-treated cells in a dose-dependent manner, but the reversal was partial, suggesting that the reduction of the GTP pool contributed to the antiviral activity of 3f, but it was not the main operative mechanism. The comparison of 3f with two other viral RNA inhibitors, ribavirin and mycophenolic acid, showed that ribavirin did not act against JUNV through the cellular enzyme inosine monophosphate dehydrogenase (IMPDH) inhibition whereas the anti-JUNV activity of mycophenolic acid was mainly targeted at this enzyme. © 2011 Elsevier B.V. |
| format |
JOUR |
| author |
Sepúlveda, C.S. García, C.C. Fascio, M.L. D'Accorso, N.B. Docampo Palacios, M.L. Pellón, R.F. Damonte, E.B. |
| author_facet |
Sepúlveda, C.S. García, C.C. Fascio, M.L. D'Accorso, N.B. Docampo Palacios, M.L. Pellón, R.F. Damonte, E.B. |
| author_sort |
Sepúlveda, C.S. |
| title |
Inhibition of Junin virus RNA synthesis by an antiviral acridone derivative |
| title_short |
Inhibition of Junin virus RNA synthesis by an antiviral acridone derivative |
| title_full |
Inhibition of Junin virus RNA synthesis by an antiviral acridone derivative |
| title_fullStr |
Inhibition of Junin virus RNA synthesis by an antiviral acridone derivative |
| title_full_unstemmed |
Inhibition of Junin virus RNA synthesis by an antiviral acridone derivative |
| title_sort |
inhibition of junin virus rna synthesis by an antiviral acridone derivative |
| url |
http://hdl.handle.net/20.500.12110/paper_01663542_v93_n1_p16_Sepulveda |
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