The antiviral effect of metformin on zika and dengue virus infection

Abstract

The Dengue (DENV) and zika (ZIKV) virus infections are currently a public health concern. At present, there is no treatment or a safe and effective vaccine for these viruses. Hence, the development of new strategies as host-directed therapy is required. In this sense, Metformin (MET), an FDA-approved drug used for the treatment of type 2 diabetes, has shown an anti-DENV effect in vitro by activating AMPK and reducing HMGCR activity. In this study, MET treatment was evaluated during in vitro and in vivo ZIKV infection and compared to MET treatment during DENV infection. Our results demonstrated that MET has a broad in vitro antiviral spectrum. MET inhibited ZIKV infection in different cell lines, but it was most effective in inhibiting DENV and yellow fever virus (YFV) infection in Huh-7 cells. However, the drug failed to protect against ZIKV infection when AG129 immunodeficient mice were used as in vivo model. Interestingly, MET increased DENV-infected male mice's survival time, reducing the severe signs of the disease. Together, these findings indicate that, although MET was an effective antiviral agent to inhibit in vitro and in vivo DENV infection, it could only inhibit in vitro ZIKV infection.

Anti-flavivirus Properties of Lipid-Lowering Drugs

“…On the other hand, MET treatment effectively inhibits ZIKV replication in different cell lines (Farfan-Morales et al, 2021); MET affected the synthesis and distribution of viral proteins in the RCs and reduced viral progeny and doublemembrane structures associated with viral replication. However, the treatment fails to counteract the negative signs of the disease or increase the half-life of ZIKV-infected AG129 mice (Farfan-Morales et al, 2021).…”

“…Regarding ZIKV, the in vitro assays have demonstrated that different STAs effectively inhibit ZIKV replication (Españo et al, 2019;Farfan-Morales et al, 2021). Interestingly only lipophilic STAs showed anti-ZIKV effects, suggesting that lipophilicity is a crucial antiviral property (Españo et al, 2019).…”

“…Studies have demonstrated a strong effect of MET on numerous cancers, cardiovascular diseases, liver diseases, obesity, and neurodegenerative diseases (Lv and Guo, 2020). The excellent safety profile and lipid-lowering properties have suggested this drug can treat DENV and ZIKV infection (Figure 2A; Soto- Martín-Acebes et al, 2019;Farfan-Morales et al, 2021).…”

“…The anti-DENV effect of MET has been documented in both in vitro and in vivo assays (Soto- Farfan-Morales et al, 2021). MET treatment significantly increased (2 days) the average survival rate in DENV-infected and treated AG129 mice compared to untreated mice and reduced the severe signs of the disease (Farfan-Morales et al, 2021).…”

“…The anti-DENV effect of MET has been documented in both in vitro and in vivo assays (Soto- Farfan-Morales et al, 2021). MET treatment significantly increased (2 days) the average survival rate in DENV-infected and treated AG129 mice compared to untreated mice and reduced the severe signs of the disease (Farfan-Morales et al, 2021). It has also been reported an association between the use of MET in diabetic patients and the lower risk of suffering a severe disease caused by DENV (Htun et al, 2018), suggesting that MET treatment could attenuate and/or prevent severe forms of DENV infection.…”