Ivermectin Inhibits Bovine Herpesvirus 1 DNA Polymerase Nuclear Import and Interferes With Viral Replication

Abstract

Bovine herpesvirus1 (BoHV-1) is a major bovine pathogen. Despite several vaccines being available to prevent viral infection, outbreaks are frequent and cause important economic consequences worldwide. The development of new antiviral drugs is therefore highly desirable. In this context, viral genome replication represents a potential target for therapeutic intervention. BoHV-1 genome is a dsDNA molecule whose replication takes place in the nuclei of infected cells and is mediated by a viral encoded DNA polymerase holoenzyme. Here, we studied the physical interaction and subcellular localization of BoHV-1 DNA polymerase subunits in cells for the first time. By means of co-immunoprecipitation and confocal laser scanning microscopy (CLSM) experiments, we could show that the processivity factor of the DNA polymerase pUL42 is capable of being autonomously transported into the nucleus, whereas the catalytic subunit pUL30 is not. Accordingly, a putative classic NLS (cNLS) was identified on pUL42 but not on pUL30. Importantly, both proteins could interact in the absence of other viral proteins and their co-expression resulted in accumulation of UL30 to the cell nucleus. Treatment of cells with Ivermectin, an anti-parasitic drug which has been recently identified as an inhibitor of importin α/β-dependent nuclear transport, reduced UL42 nuclear import and specifically reduced BoHV-1 replication in a dose-dependent manner, while virus attachment and entry into cells were not affected. Therefore, this study provides a new option of antiviral therapy for BoHV-1 infection with Ivermectin.

Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen

“…25 µM ivermectin reduced the virus titer by 4 logs and inhibited virion production by~44%, but had no effect on cell viability in the studied doses. Also, ivermectin had no effect on the binding and entry of the virus into the host cell [42].…”

More than a zip code: global modulation of cellular function by nuclear localization signals

“…Disruption of the nuclear transport machinery frequently leads to diseases, such as cancer and viral infection. More than 20 nuclear transport inhibitors (e.g., importazole (targeting Importin-b) [116], leptomycin B (targeting CRM1) [117], and ivermectin (targeting Importin-a/-b pathway) [118][119][120]) have been identified, and a few are already undergoing clinical trials [121]. However, their therapeutic potential is largely limited by toxic side effects, as the NLS and nuclear transport factor interaction not only mediates nuclear transport but also contributes to a variety of biological functions.…”

How glycobiology can help us treat and beat the COVID-19 pandemic

“…Ivermectin (an anti-parasitic macrolide) revealed broad-spectrum antiviral activity ( 90 ), also evidenced against SARS-CoV-2 in in vitro assays ( 91 ) ( Table 1 and Figure 5 ). Ivermectin inhibits the formation of the importin-α (IMPα) and IMPβ1 subunits as well as dissociates the IMPα/β1 heterodimer affecting the molecular transport to host nucleus and the viral replication ( 92 ). Multiple clinical trials using Ivermectin are currently under development ( 93 ).…”