Abstract
Favipiravir (T-705) is a broad-spectrum antiviral drug that inhibits RNA viruses after intracellular conversion into its active form, T-705 ribofuranosyl 5′-triphosphate. We previously showed that T-705 is able to significantly inhibit the replication of chikungunya virus (CHIKV), an arbovirus transmitted by Aedes mosquitoes, in mammalian cells and in mouse models. In contrast, the effect of T-705 on CHIKV infection and replication in the mosquito vector is unknown. Since the antiviral activity of T-705 has been shown to be cell line-dependent, we studied here its antiviral efficacy in Aedes-derived mosquito cells and in Aedes aegypti mosquitoes. Interestingly, T-705 was devoid of anti-CHIKV activity in mosquito cells, despite being effective against CHIKV in Vero cells. By investigating the metabolic activation profile, we showed that, unlike Vero cells, mosquito cells were not able to convert T-705 into its active form. To explore whether alternative metabolization pathways might exist in vivo, Aedes aegypti mosquitoes were infected with CHIKV and administered T-705 via an artificial blood meal. Virus titrations of whole mosquitoes showed that T-705 was not able to reduce CHIKV infection in mosquitoes. Combined, these in vitro and in vivo data indicate that T-705 lacks antiviral activity in mosquitoes due to inadequate metabolic activation in this animal species.
Highlights
Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an antiviral drug that has been approved in Japan for the treatment of pandemic influenza virus infections
Since mosquitoes are considered as lacking a homologue of the hypoxanthine guanine phosphoribosyl transferase (HGPRT) gene [20], we hypothesized that T-705 would be antivirally inactive in mosquito-derived cells and, unable to suppress virus replication in mosquitoes
Since chikungunya virus (CHIKV) does not induce a cytopathic effect (CPE) in mosquito cells, antiviral efficacy was assessed by the reduction in intracellular viral RNA, as quantified by quantitative reverse transcription PCR (qRT-PCR), and the reduction of infectious virus progeny in the supernatant, as determined by end-point titrations
Summary
Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an antiviral drug that has been approved in Japan for the treatment of pandemic influenza virus infections. It is a nucleobase analog which is converted intracellularly into its active, phosphoribosylated form, T-705-RTP. This active molecule behaves as a pseudo-purine and is incorporated into the growing viral RNA chain by the viral RNA-dependent RNA polymerase (RdRp), which may lead to either chain termination or lethal virus mutagenesis or a combination of both [1,2]. T-705 has been studied for the treatment of SARS-CoV-2 infections [13,14]
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