Journal
FRONTIERS IN MICROBIOLOGY
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fmicb.2022.979904
Keywords
trifluoperazine; antiviral drugs; eIF2 alpha; PKR-like endoplasmic reticulum kinase (PERK); calmodulin
Categories
Funding
- National Natural Science Foundation of China
- [81902845]
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Virus-related diseases pose a serious threat to human health, but there are limited antiviral drugs available. This study found that the antipsychotic drug trifluoperazine (TFP) inhibits the replication of vesicular stomatitis virus and herpes simplex virus type 1 through a specific mechanism.
Virus-related diseases are seriously threatening human health, but there are currently only 10 viruses with clinically approved antiviral drugs available. As non-cellular organisms, viruses parasitize in living cells and rely on the protein synthesis mechanism of the host cells. In this study, we found that the antipsychotic drug trifluoperazine (TFP), a dual dopamine receptor D2 (DRD2)/calmodulin (CALM) antagonist, increases the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2 alpha), a key factor in the regulation of protein synthesis and significantly inhibits vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1) replication. CALM but not DRD2 is involved in the antiviral activity of TFP. By knockdown of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) we found that the antiviral function of TFP is dependent on PERK, a stress response kinase that mediates eIF2 alpha phosphorylation. Furthermore, the results of animal experiments showed that TFP protects mice from lethal VSV attacks, improving the survival rate and reducing lung injury. Taken together, these data suggests that TFP inhibits virus replication through PERK-eIF2 alpha axis, and this broad-spectrum of mechanisms are worth further evaluation in clinical trials in the future.
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