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 (Madjid et al., 2020). 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 dosage ( Toljan and Vrooman, 2018; Younger et al., 2014; Low-Dose Naltrexone for Pruritus in Systemic Sclerosis, XXXX ).
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 (Walls et al., 2020). 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 fusion (Walls et al., 2020). Spike structural integrity and cleavage activation play a key role in virus invasion and virulence (Lu et al., 2020; Walls et al., 2020). 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 (Hussain, 2020). 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 been reported (Lan et al., 2020). 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 group (Lan et al., 2020).
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 virulence (Walls et al., 2020). Based on virtual screening results, LDN interacts with ACE2. Naltrexone prefers to bind in the central 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(Zha, 2020). 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 clearance (Stockman et al., 2006). Combination of antibiotic, antiviral and steroid therapy exhibited respiratory failure and required non-invasive ventilation (Wu et al., 2020). Elevated plasma IL-6 levels have been reported and to be predictive of a fatal outcome in COVID-19 patients (Coperchini et al., 2020; Zhao, 2020). 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 blocks its signaling cascade (Tanaka et al., 2016). However, clinical experience with tocilizumab in viral disease is very limited. Moreover, high costs and safety risks may be a barrier to the wide use of tocilizumab in the treatment of COVID-19.
Naltrexone hydrochloride is an FDA-approved non-peptide opioid antagonist (Cornish et al., 1997). In 1995, the FDA approved 50 mg naltrexone (ReVia) for the treatment of alcohol addiction. Low Dose Naltrexone (LDN; dose between 1 and 5 mg) is an immune-modulator, and a known TLR4 and opioid receptor antagonist (Cant et al., 2017; Hutchinson et al., 2008; Wang et al., 2016). Although naltrexone was synthesized as an orally active competitive opioid receptor antagonist, however, LDN exhibits paradoxical properties, including analgesia and anti-inflammatory actions, where, LDN simultaneously has an antagonist effect on non-opioid receptors (TLR4) which have not been reported at higher doses (Cant et al., 2017; Hutchinson et al., 2008; Wang et al., 2016; Younger et al., 2014). Unlike high doses of naltrexone, LDN has several mechanisms of action reported in the literature (The Uses of Low-Dose Naltrexone in Clinical Practice, 2020). LDN stimulates the release of β-endorphins by acting on the opioid receptor (Gold et al., 1982; The Uses of Low-Dose Naltrexone in Clinical Practice, 2020). LDN acts as a TLR4 antagonist, in a human pilot study (4.5 mg of LDN daily) significantly reduced serum pro-inflammatory cytokines (IL)-1, IL-2, IL-12, IL-18, etc (Parkitny and Younger, 2017). 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 an immunomodulatory agent and may be considered for use in combination with antiviral drugs or hydroxychloroquine 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 hydroxychloroquine or an antiviral agent may give physicians more time to provide supportive treatment for patients with COVID-19.