Antiviral Effects of Geranylgeranylacetone: Enhancement of MxA Expression and Phosphorylation of PKR during Influenza Virus Infection

Abstract

A cyclic polyisoprenoid compound, geranylgeranylacetone (GGA), has been used as antiulcer drug. GGA is also a potent inducer of heat shock proteins (HSPs). HSPs are considered to induce an antiviral effect; however, the detailed mechanism is unknown. To determine whether GGA might show antiviral activity and what the mechanism is, the effect of GGA against influenza virus (strain PR8) infection in vivo and in vitro was investigated. The results demonstrated that GGA treatment strongly suppressed the deleterious consequences of PR8 replication and was accompanied by an increase in HSP70 gene expression in mice. Results from in vitro analyses demonstrated that GGA significantly inhibited the synthesis of PR8-associated proteins and prominently enhanced expression of human myxovirus resistance 1 (MxA) followed by increased HSP70 transcription. Moreover, GGA augmented the expression of an interferon-inducible double-strand RNA-activated protein kinase (PKR) gene and promoted PKR autophosphorylation and concomitantly ␣ subunit of eukaryotic initiation factor 2 phosphorylation during PR8 infection. It is proposed that GGA-induced HSP70 has potent antiviral activity by enhancement of antiviral factors and can clinically achieve protection from influenza virus infection.

Geranylgeranylacetone inhibits lysophosphatidic acid‐induced invasion of human ovarian carcinoma cells in vitro

“…26 We have shown that alendronate, which inhibits osteoclast activity, also inhibits LPAinduced cancer cell invasion by preventing the geranylgeranylation of Rho. 13 Thus, geranylgeranylation of small G proteins is essential not only in osteoclast activity, but also in cancer cell invasion.…”

“…Laboratory data revealed no detrimental events, even at the massive dosage of 500 mg/kg of body weight. 26 Whereas GGA may have therapeutic potential in the treatment of ovarian carcinoma, in vivo studies are needed to confirm its efficacy especially in the peritoneal dissemination model.…”

Geranylgeranylacetone, an Inducer of the 70-kDa Heat Shock Protein (HSP70), Elicits Unfolded Protein Response and Coordinates Cellular Fate Independently of HSP70

“…The therapeutic utility of GGA in vivo has also been documented by several investigators. For example, administration with GGA attenuated not only gastric mucosal damage but also ischemic brain injury, viral infection, and endotoxin shock (Unoshima et al, 2003;Nakada et al, 2005;Uchida et al, 2006). However, it is currently unclear whether these therapeutic effects of GGA are ascribed only to up-regulation of HSP70.…”

Loss of stress response as a consequence of viral infection: implications for disease and therapy

“…Similarly, geranylgeranylacetone (GGA), an Hsp inducer, is effective as an antiviral in treating influenza A infection. GGA limits viral replication, blocks synthesis of the virulent viral protein NS1, and limits weight loss and pulmonary infiltration (Unoshima et al 2003). GGA has been used clinically for decades to treat gastric ulcers, is safe in humans, and inexpensive.…”