In vitro and in vivo efficacy of Metformin against dengue

Dengue is a prevalent mosquito-borne viral infection in the tropical and sub-tropical regions. Its potential to progress into severe, life-threatening disease, has pressed the research community to develop safe, effective and affordable antivirals. Metformin (MET), a first-line antidiabetic drug and indirect AMP-activated protein kinase (AMPK) activator, has recently emerged as a potential anti-DENV therapeutic candidate, based on some experimental evidence supporting anti-DENV activity in vitro and widely reported anti-inflammatory properties. Here, we examined MET in vitro activity against the four DENV serotypes and in two different mammalian cell lines. MET displayed a poor anti-DENV activity in BHK-21 cells with IC50 in the mM range, which was associated with increased p-AMPK alpha levels, thereby supporting that MET antiviral activity is mediated through AMPK activation. In contrast, MET exerted a pro-DENV activity in Vero cells that did not correlate with increased AMPK activation, suggesting AMPK-independent effects. Treatment with compound 991, a direct AMPK activator, led to reduced viral titers against all four serotypes and across both mammalian cell lines. In vivo, oral administration of MET did not reduce viremia titers in an asymptomatic mouse model, neither did it improve disease severity and progression in a mouse model of severe dengue. Instead, high dose regimen worsened disease outcome as evidenced by increased mortality, higher viremia and hyper-inflammation. Therefore, while AMPK may represent a potential host target, MET does not seem to hold great promise as a pan-serotype anti-dengue drug.