Introduction
Coronavirus disease 2019 (COVID-19) is a major health concern, clinical
symptoms of the disease vary from a mild illness, acute respiratory
issues to multi-organ failure 1,2. Older age,
diabetes, cardiac diseases predict poor prognosis in COVID-19 patients3,4. Although much is known about the mortality of the
COVID-19, however, details of the cellular responses to this virus are
not known.
Several preclinical and clinical trials data have indicated an elevated
cytokine/chemokine response in severe COVID-19 patients and identifies
cytokine storm as the most potentially dangerous event for mortality5–7. Several kinases in the MAPK/ERK
(mitogen-activated protein kinases/extracellular signal-regulated
kinases) pathway are essential for viral replication. ERK1 and ERK2
phosphorylate HIV-1 proteins and enhance viral
infectivity8. The phosphorylation status of ERK1/2 is
positively correlated with virus load and ERK1/2 inhibition suppressed
viral replication and viral infectivity8. Some
preclinical findings have suggested targeting ERK1/2 pathway to halt the
viral replication and severity of SARS-COV-29.
SARS-CoV-2 uses the homotrimeric spike glycoprotein as the main protein
that interacts with the host by binding to host cell receptors (ACE2) to
mediate virus invasion for cell entry. Some recent studies have
highlighted the important role of ACE2 in mediating entry of
SARS-CoV-210,11. A recent report also recognized
several critical residues in RBD, including its receptor-binding motif
(RBM) that directly contacts with human ACE212. In
vitro study using HeLa cells also reinforced the role of ACE2 in
mediating entry of SARS-CoV-2, where HeLA cells expressing ACE2 are
susceptible to SARS-CoV-2 infection whereas those without ACE2 are not.
Furthermore, In vitro binding measurements, experiments showed that the
SARS-CoV-2 RBD binds to ACE2 with an affinity in the nanomolar range,
indicating that the RBD is a key functional component that is
responsible for the binding of SARS-CoV-2 by ACE2 and can be considered
as a target for the treatment of coronavirus infection to block
SARS-CoV-2 from entering host cells11,12.
There is a very fast ongoing search for therapeutics acting on
SARS-CoV-2. Depending on the activity, the therapies can be divided into
majorly main categories: (1) Inhibiting the viral RNA synthesis and
replication, (2) Deterring the virus from binding to human cell ACE2
receptors, (3) Reinstating the innate immunity, and (4) Blocking the
host’s specific receptors or enzymes. Despite many experimental and
computational studies currently exploring all of these categories, to
date, there is no confirmed effective treatment specifically available
for COVID-19.
In this study, we report that the FDA-approved non-peptide
opioid antagonist drug13, LDN suppresses high fat/LPS
induced pro-inflammatory cytokine release both from macrophage cells and
Adipose tissue macrophage (ATM). LDN also showed activity as an ERK1/2
inhibitor. Moreover, virtual docking and simulation data also suggest
LDN may disrupt the interaction of ACE2 with RBD. As a reliable COVID-19
vaccine is unlikely to available before the maximal infection of
COVID-19 has occurred, it is essential to establish therapeutics for the
COVID-19 patients, based on our data, we proposed FDA-approved LDN can
be used in combination or as an adjuvants therapy to treat mild to
moderate symptomatic COVID-19 patients