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].