Genistein treatment of cells inhibits arenavirus infection

Abstract

Arenaviridae is a family of enveloped viruses some of which are capable of causing hemorrhagic fever syndromes in humans. In this report, we demonstrate that treatment of host cells with the tyrosine kinase inhibitor genistein inhibits infection of cells with the New World arenavirus Pichindé (PICV). The greatest degree of inhibition was observed in pre-treated target cells, but modest inhibition of infection was also seen when drug was added to cultures up to 48h after infection. We show that PICV-induced phosphorylation of the activating transcription factor-2 protein (ATF-2) and cyclic adenosine monophosphate response element binding protein (CREB) is inhibited following genistein treatment. Lastly, genistein treatment also inhibited transduction of cells with pseudotyped retrovirus particles expressing envelope proteins of the Old World arenavirus Lassa virus. These results demonstrate that kinase activity is required for arenavirus infection and that therapeutics designed to inhibit kinase activity should be explored.

Attenuated and Lethal Variants of Pichindé Virus Induce Differential Patterns of NF-κB Activation Suggesting a Potential Target for Novel Therapeutics

“…In contrast, as pathogenesis late in infection correlates with high levels of pro-inflammatory cytokines, using a different set of inhibitors at later stages of disease to inhibit NF-kB p65=p50 may provide protection. In addition to targeting immune pathways, inhibition of other cellular pathways may be effective in controlling viral replication directly (26,27). We believe that this type of approach, modulating specific ''arms'' of the host-response at different stages of infection, in combination with supportive care and drugs that directly target pathogen replication, may 460 BOWICK ET AL.…”

Receptor Tyrosine Kinase Inhibitors Block Multiple Steps of Influenza A Virus Replication

“…Host signaling through RTKs and other tyrosine kinases has also been shown to play important roles in virus replication. The tyrosine kinase inhibitor genistein was found to block replication of HIV-1, herpes simplex virus type 1 (HSV-1), and arenavirus (51,53,61), for example, and Src family kinases are known to be important for assembly and maturation of dengue virus and West Nile virus (6,19). The Raf/MEK/ERK (42) and PI3K/Akt (9, 10, 15) pathways downstream of RTKs play important roles in influenza virus replication.…”

Yet another ten stories on antiviral drug discovery (part D): Paradigms, paradoxes, and paraductions

“…170 The mechanism of action of geneticin has remained enigmatic. Curiously, it looses its antiviral activity when guanidinylated (gG418) 170 [geneticin should not be confused with the phytoestrogen genistein, a tyrosine kinase inhibitor that has been shown to inhibit arenavirus infection 171 ]. Unique small molecule entry inhibitors (Fig.…”