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.