COVID-19: a lesson to be learned.
The SARS-CoV-2 pandemic has been generated by a new strain of the
coronavirus that has
never previously been identified in humans. This
virus is phylogenetically close to SARS-CoV, the causative agent of
SARS. SARS-CoV-2, which reached humans via
a spillover process from
other animal species, possesses
a peculiar tropism for the airway
epithelium in humans, showing also elevated contagiousness and an
extremely variable clinical course of its infection.
The COVID-19
outbreak found the world definitely unprepared to handle such a global
emergency. Similar concerns must be raised toward a potential novel
strain possibly responsible for future viral outbreaks, in order not to
replicate the extremely negative outcome of the influenza A H1N1
1918–1919 “Spanish” pandemic [
97].
To this end, it is mandatory to work prospectively to produce or
identify better antiviral drugs and prophylactic/therapeutic MoAb
therapies, as well as possibly targeting vital pathogenic factors, such
as, in the case of SARS-CoV-2, Spike protein RBD [
36,
98] or the main protease M
pro [
99] (nsp5).
In addition, a study on the immune response of patients that have
recovered from SARS-CoV-2 infection could be of great interest, in line
with what was carried out for the Ebola survivors [
100].
The
forcedly limited number of drugs briefly described in this review
appear to act essentially through selected mechanisms, i.e.,
a) inhibition of the PI3K/AKT–SGK1/mTOR signaling cascade;
b) inhibition of
the cytokine storm; and
c) inhibition of viral nucleic acid synthesis.
The activation of the PI3K/AKT–SGK1/mTOR pathway appears fundamental for
supporting the replication of various virus species in the host [
17,
18,
19,
20] by boosting their energy metabolism and reactive oxygen species production, especially in the cells of the immune system [
101,
102].
Therefore, drugs able to interfere with mTORC1 signaling can produce
ATP shortage in the cells in which the virus is replicating,
characterized by an excess of energy requirements. Such a metabolic
pattern is reminiscent of the peculiar setup of the energy metabolism in
cancer cells, i.e. Warburg effect [
103,
104], where a pivotal role is played by the PI3K/AKT–SGK1/mTOR signaling cascade [
10,
105,
106].
Given
the above, it is not surprising that all the non-specific antiviral
drugs here described, i.e. the anticancer drugs repositionable in
COVID-19 therapy deal with energy metabolism and inflammation.
A
set of the drugs described here, e.g. those with explicit
antiviral
effect, can be preferred for the
early stages of SARS-CoV-2 infection,
while those dedicated to
restraining the cytokine response – and without
explicit antiviral effect - should be employed, if necessary,
at later
time points.
Anyway, we should always consider that, even if the
medications discussed in this review are safely in use in the clinics,
the final decision for their administration in COVID-19 for
compassionate and urgent use, when in the absence of validated clinical
trials, should be taken solely after collegial approval by the clinical
team taking care of the patient and under strict clinical surveillance.
Indeed, unpredictable toxic side effects can arise, possibly linked with
the patient clinical status or to the simultaneous administration of
other drugs.
Finally, an interesting evaluation on how COVID-19
pandemic will affect the clinical care in the seven comprehensive cancer
centers of Cancer Core Europe is discussed in a timely paper [
107].
The authors illustrate appropriate guidelines that can transform this
pandemic into an opportunity, e.g. for the assessment of the clinical
effects of de-escalating anticancer regimens, forcedly imposed in order
to
prevent or reduce iatrogenic neutropenia and lymphopenia.
We
hope that these findings may pave the way for a more comprehensive
clinical experimentation on repurposing of ‘old’ drugs to the treatment
of COVID-19, a line of research sustained by scant funds but of prime
importance to face this new worldwide challenge.
