BIGUANIDES: NEW ANTIVIRAL TOOL?
The search for the antiviral activity of biguanides is not recent. Still in the 60’s, the broad spectrum of action of this pharmacological class was already being noticed [8,9]. From several experiments, anti-helmintic, antiviral and antimalarial effects were identified. However, it was found that the high doses necessary for the antiviral activity of the modified biguanides made the clinical use of the compounds known at that time impracticable [8]. In the last decade, several studies have been carried out in order to verify the effect of biguanides in the aid of antiviral therapies, with MET as the main representative. Some of these studies approach the benefits of the drug in the antiviral treatment indirectly, due to its ability to reduce the body’s resistance to insulin, which ends up improving body defenses. It was verified that in patients co-infected with HIV and HCV, whose metabolic and/or inflammatory variables were significantly altered, the treatment with MET was well tolerated and significantly increased the sensitivity of peripheral tissues to insulin [37]. Very beneficial effect since viral infections affect glucose metabolism, leading to insulin resistance and development of DM2 in predisposed individuals [38].
By adding MET to alphapeginterferon-2a and ribavirin treatment in individuals with chronic Hepatitis C genotype 1 and insulin resistance, there was an improvement in insulin sensitivity. Additionally, the treatment increased the sustained viral response rate of patients with a good safety profile [39].
A quasi-experimental study selected 138 individuals with chronic hepatitis C who presented insulin resistance and divided three groups: A, treated with interferon and ribavirin; B, plus MET; and C interferon, ribavirin and pioglitazone. After 48 weeks, the sustained viral response was higher in B (p = 0.003) [40].
When used in combination with lamivudine or interferon alpha-2b, MET increased inhibition of surface antigen expression and replication of hepatitis B virus, ratifying the possibility of synergism with other antivirals [41].
An in vitro study found that, compared with non-infected control cells, ZIKV infection resulted in decreased AMPK in endothelial cells (dengue and hepatitis C viruses are also known to inhibit AMPK activation). Consequently, ZIKV-infected cells were exposed to AMPK pharmacological activators (such as AICAR) and MET. These compounds did not exert direct antiviral activity nor impaired viral adsorption/entry, but reduced (p < 0.001) ZIKV infection. According to the authors, AMPK activation exerts a powerful antiviral response that restricts replication in infected endothelial cells by inhibiting glycolysis induced by ZIKV, an essential source of energy and basic elements for replication. Additionally, this activation enhances the innate antiviral response in ZIKV-infected cells. It is worth noting, however, that the compound AICAR inhibited the replication of ZIKV at a higher rate compared to MET (p < 0.001) [42].
The activation of AMPK inhibits the protein kinase mTOR. This effect provoked by biguanides can also bring benefits on antiviral therapies. It was verified that the mitogenic stimulation caused by mTOR accelerates mortality induced by influenza in animals, increasing the susceptibility of alveolar cells type II to infection. Due to the inhibitory property of mTOR, it was suggested the use of biguanides for the treatment of influenza [43].
In order to avoid lactic acidosis, the use of inhaled pharmaceutical forms for treatment has been proposed. However, an important aspect emphasized by the authors regarding this form of administration was that the inhaled MET could require a large amount of powder delivery to the lungs, resulting in reduced complacency, bronchospasm and cough. BUF was pointed out as an adequate substitute, because it has eight times more potency than MET, making possible to reduce the amount of particulate material delivered to the lungs and reducing the occurrence of lactic acidosis as an adverse effect [43].
A study whose objective was to verify drugs with potential to be used in the treatment of pregnant women with COVID-19 cites the use of MET in the therapy directed to the host. This type of therapy aims at activating the body’s protective immune response and suppressing the overactive inflammatory response. This method is considered safe and effective, capable of reducing the immunopathology and improving the immune response, in addition to being suitable for pregnant women with the disease [44].