Abstract
The guanabenz derivative Sephin1 has recently been proposed to increase the levels of translation initiation factor 2 (eIF2α) phosphorylation by inhibiting dephosphorylation by the protein phosphatase 1—GADD34 (PPP1R15A) complex. As phosphorylation of eIF2α by protein kinase R (PKR) is a prominent cellular antiviral pathway, we evaluated the consequences of Sephin1 treatment on virus replication. Our results provide evidence that Sephin1 downregulates replication of human respiratory syncytial virus, measles virus, human adenovirus 5 virus, human enterovirus D68, human cytomegalovirus, and rabbit myxoma virus. However, Sephin1 proved to be inactive against influenza virus, as well as against Japanese encephalitis virus. Sephin1 increased the levels of phosphorylated eIF2α in cells exposed to a PKR agonist. By contrast, in virus-infected cells, the levels of phosphorylated eIF2α did not always correlate with the inhibition of virus replication by Sephin1. This work identifies Sephin1 as an antiviral molecule in cell culture against RNA, as well as DNA viruses belonging to phylogenetically distant families.
Highlights
Most clinically available antiviral drugs act by directly targeting viral components to inhibit a critical step in the viral life cycle, such as entry, replication, or viral egress [1]
Cellular viability remained above 75% in all cell lines tested, with the exception of ARPE-19 cells, which had a 40% decrease in viability. This result demonstrates that, the molecule had to be used at a high dose to reach a significant antiviral effect, inhibition of virus replication could not be attributable to alterations in cellular viability
Secondary structures found in the RNA of some positive strand RNA viruses, such as viruses belonging to the Togaviridae family, Reoviridae family and hepatitis C virus, allow translation of these RNAs to proceed normally, or in some cases better, in the presence of high levels of eIF2α phosphorylation [12]
Summary
Most clinically available antiviral drugs act by directly targeting viral components to inhibit a critical step in the viral life cycle, such as entry, replication, or viral egress [1]. These molecules have several advantages, as they can be very potent inhibitors and should have minor side effects because they are, in theory, virus specific. Antiviral molecules targeting host functions that are necessary for the virus life cycle are less likely to lead to the emergence of resistant viral mutants [3]. Broadspectrum antiviral molecules can be developed if the targeted host cell function regulates the replication of a wide range of viruses. In an effort to limit toxicity, it is necessary to target a host cell function that is not crucial to the cell physiology and/or that is more specific to infected cells
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