Antiviral activity of A771726, the active metabolite of leflunomide, against Junín virus
The aim of this study was to investigate the effect of A771726, the active metabolite of leflunomide, (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad against the infection with Junín virus (JUNV), agent of Argentine hemorrhagic fever (AHF). The treatment...
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2018
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_01466615_v90_n5_p819_Sepulveda http://hdl.handle.net/20.500.12110/paper_01466615_v90_n5_p819_Sepulveda |
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paper:paper_01466615_v90_n5_p819_Sepulveda2023-06-08T15:12:33Z Antiviral activity of A771726, the active metabolite of leflunomide, against Junín virus A771726 antiviral activity arenavirus host target leflunomide pyrimidine inhibitor dihydroorotate dehydrogenase drug metabolite orotic acid pyrimidine ribavirin teriflunomide uridine virus RNA A-549 cell line animal cell antiviral activity Article cell viability controlled study drug effect drug efficacy drug mechanism drug response drug structure enzyme activity human human cell Junin virus nonhuman real time polymerase chain reaction RNA synthesis treatment outcome virus replication virus strain The aim of this study was to investigate the effect of A771726, the active metabolite of leflunomide, (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad against the infection with Junín virus (JUNV), agent of Argentine hemorrhagic fever (AHF). The treatment with non-cytotoxic concentrations of A771726 of Vero and A549 cells infected with JUNV inhibited virus replication in a dose-dependent manner, as determined by virus yield reduction assay. The antiviral effectiveness of A771726 was not importantly affected by the multiplicity of infection and the virus strain. Moreover, the combination of A771726 and ribavirin had a significantly more potent antiviral activity than each single drug treatment. Mechanistic studies showed that the main action of A771726 is exerted before 6 h of JUNV infection. Accordingly, inhibition of viral RNA synthesis was detected in treated infected cells by real time RT-PCR. The exogenous addition of uridine or orotic acid produced a partial reversal of the inhibitory effect of A771726 on infective virus production whereas a total reversion was detected on JUNV RNA synthesis, probably by restoration of the enzymatic activity of dihydroorotate dehydrogenase (DHODH) and the intracellular pyrimidine pools. In conclusion, these results suggest that the antiviral target would be viral RNA synthesis through pyrimidine depletion, but any other effect of the compound on JUNV infection cannot be excluded. This study opens the possibility of the therapeutic application of a wide spectrum host-targeted compound alone or in combination with ribavirin to combat AHF as well as other human pathogenic arenaviruses. © 2018 Wiley Periodicals, Inc. 2018 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_01466615_v90_n5_p819_Sepulveda http://hdl.handle.net/20.500.12110/paper_01466615_v90_n5_p819_Sepulveda |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
A771726 antiviral activity arenavirus host target leflunomide pyrimidine inhibitor dihydroorotate dehydrogenase drug metabolite orotic acid pyrimidine ribavirin teriflunomide uridine virus RNA A-549 cell line animal cell antiviral activity Article cell viability controlled study drug effect drug efficacy drug mechanism drug response drug structure enzyme activity human human cell Junin virus nonhuman real time polymerase chain reaction RNA synthesis treatment outcome virus replication virus strain |
| spellingShingle |
A771726 antiviral activity arenavirus host target leflunomide pyrimidine inhibitor dihydroorotate dehydrogenase drug metabolite orotic acid pyrimidine ribavirin teriflunomide uridine virus RNA A-549 cell line animal cell antiviral activity Article cell viability controlled study drug effect drug efficacy drug mechanism drug response drug structure enzyme activity human human cell Junin virus nonhuman real time polymerase chain reaction RNA synthesis treatment outcome virus replication virus strain Antiviral activity of A771726, the active metabolite of leflunomide, against Junín virus |
| topic_facet |
A771726 antiviral activity arenavirus host target leflunomide pyrimidine inhibitor dihydroorotate dehydrogenase drug metabolite orotic acid pyrimidine ribavirin teriflunomide uridine virus RNA A-549 cell line animal cell antiviral activity Article cell viability controlled study drug effect drug efficacy drug mechanism drug response drug structure enzyme activity human human cell Junin virus nonhuman real time polymerase chain reaction RNA synthesis treatment outcome virus replication virus strain |
| description |
The aim of this study was to investigate the effect of A771726, the active metabolite of leflunomide, (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad against the infection with Junín virus (JUNV), agent of Argentine hemorrhagic fever (AHF). The treatment with non-cytotoxic concentrations of A771726 of Vero and A549 cells infected with JUNV inhibited virus replication in a dose-dependent manner, as determined by virus yield reduction assay. The antiviral effectiveness of A771726 was not importantly affected by the multiplicity of infection and the virus strain. Moreover, the combination of A771726 and ribavirin had a significantly more potent antiviral activity than each single drug treatment. Mechanistic studies showed that the main action of A771726 is exerted before 6 h of JUNV infection. Accordingly, inhibition of viral RNA synthesis was detected in treated infected cells by real time RT-PCR. The exogenous addition of uridine or orotic acid produced a partial reversal of the inhibitory effect of A771726 on infective virus production whereas a total reversion was detected on JUNV RNA synthesis, probably by restoration of the enzymatic activity of dihydroorotate dehydrogenase (DHODH) and the intracellular pyrimidine pools. In conclusion, these results suggest that the antiviral target would be viral RNA synthesis through pyrimidine depletion, but any other effect of the compound on JUNV infection cannot be excluded. This study opens the possibility of the therapeutic application of a wide spectrum host-targeted compound alone or in combination with ribavirin to combat AHF as well as other human pathogenic arenaviruses. © 2018 Wiley Periodicals, Inc. |
| title |
Antiviral activity of A771726, the active metabolite of leflunomide, against Junín virus |
| title_short |
Antiviral activity of A771726, the active metabolite of leflunomide, against Junín virus |
| title_full |
Antiviral activity of A771726, the active metabolite of leflunomide, against Junín virus |
| title_fullStr |
Antiviral activity of A771726, the active metabolite of leflunomide, against Junín virus |
| title_full_unstemmed |
Antiviral activity of A771726, the active metabolite of leflunomide, against Junín virus |
| title_sort |
antiviral activity of a771726, the active metabolite of leflunomide, against junín virus |
| publishDate |
2018 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_01466615_v90_n5_p819_Sepulveda http://hdl.handle.net/20.500.12110/paper_01466615_v90_n5_p819_Sepulveda |
| _version_ |
1768542499715940352 |