Abstract
There are currently no antiviral agents for human metapneumovirus (HMPV), respiratory syncytial virus (RSV), mumps virus (MuV), or measles virus (MeV). Favipiravir has been developed as an anti-influenza agent, and this agent may be effective against these viruses in vitro. However, the molecular mechanisms through which the agent affects virus replication remain to be fully elucidated. Thus, to clarify the detailed molecular interactions between favipiravir and the RNA-dependent RNA polymerase (RdRp) of HMPV, RSV, MuV, MeV, and influenza virus, we performed in silico studies using authentic bioinformatics technologies. As a result, we found that the active form of favipiravir (favipiravir ribofuranosyl-5′-triphosphate [F-RTP]) can bind to the RdRp active sites of HMPV, RSV, MuV, and MeV. The aspartic acid residue of RdRp active sites was involved in the interaction. Moreover, F-RTP was incorporated into the growing viral RNA chain in the presence of nucleotide triphosphate and magnesium ions. The results suggested that favipiravir shows two distinct mechanisms in various viruses: RdRp active site inhibition and/or genome replication inhibition.
Highlights
Most antiviral agents inhibit genome replication or proteases and prevent viral entry of a target virus [1,2]
Our previous report showed that favipiravir ribofuranosyl-5′-triphosphate (F-RTP) binds near the tunnel of influenza RNA-dependent RNA polymerase (RdRp) and could bind to RdRp active sites in coronavirus [48]. This result is consistent with the present study, whereas we newly showed that the RdRp active sites residues in coronavirus were different from those in Human metapneumovirus (HMPV), respiratory syncytial virus (RSV), mumps virus (MuV), and measles virus (MeV)
We performed a precise analysis of the molecular interaction between favipiravir and the RdRp of HMPV, RSV, MuV, MeV, and influenza virus using in silico methods
Summary
Most antiviral agents inhibit genome replication or proteases and prevent viral entry of a target virus [1,2]. Nucleic acid analogs are an example of agents that inhibit viral genome replication [3]. These agents lead to the termination of genome replication or inhibit polymerase activity [3]. Favipiravir (6-fluoro-3-hydroxypyrazine-2-carboxamide, Avigan®) was synthesized as an anti-influenza agent and is classified as a nucleic acid analog [9]. Favipiravir has been reported to inhibit influenza virus genome replication [10,11]. Previous reports showed that favipiravir inhibited other viral replications, including norovirus, Ebola virus, HMPV, RSV, MuV, and MeV, in cell culture systems [12,13,14,15]. In silico approaches in drug discovery allow us to screen large numbers of compounds virtually in a short period of time, reducing the initial cost of hit identification and increasing the likelihood of finding a drug candidate of interest
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