Discussion:
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 individuals at moderate and high risk of the
disease. So far, anti-viral medication is a major available option for
COVID19 patients. LDN which showed properties like anti-inflammatory,
ERK1/2 inhibitory, and as well virtual docking and simulation data also
suggested LDN may disrupt the interaction of ACE2 with RBD. LDN has been
gaining credibility in its ability to halt the progression of several
diseases without significant side effects when administered in low
dosage18–22.
Spike is the main structural protein of coronavirus and assembles into a
special corolla structure on the surface of the virus as a trimer. Spike
is the main protein that interacts with the host by binding to host cell
receptors to mediate virus invasion. Spike is cleaved into S1 and S2 by
the host cell protease like TMPRSS2, etc. The main function of S1 is to
bind with host cell surface receptor; ACE2 and the S2 subunit mediates
virus-cell and cell-cell membrane fusion11. Spike
structural integrity and cleavage activation play a key role in virus
invasion and virulence11,23. Therapeutic strategies to
block coronavirus from entering host cells by targeting Spike proteins
or specific receptors (ACE2) on the host surface are valuable for the
development of anti-viral drugs. It is anticipated that potential ACE2
inhibitors may not be suitable to use as drugs for treating SARS-CoV-2
infection because the poor prognosis would be induced by the inhibition
of ACE2 enzyme activities, considering ACE2 is a protective role against
lung injury. Recently, the crystal structure of the receptor-binding
domain (RBD) of the spike protein of SARS-CoV-2 bound to the cell
receptor ACE2 has reported12. Lan et al mentioned
there are 13 hydrogen bonds at the SARS-CoV-2 RBD–ACE2 interface, this
involves multiple tyrosine residues (Tyr436, Tyr449, Tyr489, and Tyr505)
from the SARS-CoV-2 RBD to form hydrogen-bonding interactions with the
polar hydroxyl group12.
The latest research further strengthened that the spike-RBD sequence of
SARS-CoV-2 interacts with host receptor ACE2 and this RBD-ACE2 complex
plays a key role in virus invasion and virulence11.
Based on virtual screening results, LDN interacts with ACE2. Naltrexone
prefers to bind in the cavity formed SARS-CoV-2 RBD and ACE2 receptor.
Tyr505 and Glu406 of RBD formed two crucial hydrogen bonds with the
naltrexone with an atomic distance of 2.08 and 1.80, while, Arg403
formed electrostatic contact. While the His34, Glu37, and Phe390 of ACE2
displayed some hydrophobic contacts (mostly pi-alkyl contacts) with
naltrexone. Overall this suggests LDN can strongly interact with
SARS-CoV-2 RBD, including its RBM may further influence RDB- ACE2
binding, and host cell infectivity.
Therapeutic options for severe COVID-19 remain limited to date,
Immunomodulatory agents that directly target the crucial cytokines
involved in COVID-19 may also help in alleviating hyperinflammation
symptoms, mild and severe cases in particular 24.
Corticosteroids are among the most commonly used drugs for
immunomodulatory therapy of infectious diseases. However, the use of
corticosteroids in the treatment of COVID-19 can cause host immune
suppression and may delay viral clearance25.
Combination of antibiotic, antiviral and steroid therapy exhibited
respiratory failure and required non-invasive
ventilation26. Elevated plasma IL-6 levels have been
reported and to be predictive of a fatal outcome in COVID-19
patients527. Other than corticosteroids, Tocilizumab,
a specific monoclonal antibody that blocks IL-6, has been recommended
for use in severe or critically ill patients. Tocilizumab specifically
binds to IL-6 receptor, and block its signalling
cascade28. However, clinical experience with
tocilizumab in viral disease is very limited. Moreover, high costs and
safety risks may be a barrier for the wide use of tocilizumab in the
treatment of COVID-19.
Unlike high doses naltrexone, Low Dose Naltrexone (LDN; dose between 1
to 5 mg) has several mechanisms of action reported in the literature29. LDN stimulates the release of β-endorphins by
acting on opioid receptor29,30. LDN acts as a TLR4
antagonist, In human pilot study (4.5 mg of LDN daily) significantly
reduced serum proinflammatory cytokines (IL)-1, IL-2, IL-12, IL-18,
TNF-a etc31. Importantly, Low Cost, Low side effects,
no reports of LDN interactions with other medications, and oral
availability make LDN as a lucrative option to be used as
immunomodulatory agent and may be considered for use in combination with
antiviral drugs for the treatment of severe or critical cases of
COVID-19.
Our data provide a proof-of-concept for the potential feasibility of
repurposing of FDA approved non-peptide opioid antagonist; naltrexone as
host-targeted broad-spectrum antiviral therapies to combat COVID-19
infections. The next step will be to confirm data in COVID-19 patients.
LDN alone or as an adjuvant therapy with an antiviral agent may give
physicians more time to provide supportive treatment for patients with
COVID-19.