Naltrexone a potential therapeutic candidate for COVID-19

Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the cause of Coronavirus Disease (COVID-19) that has resulted in a global pandemic. At the time of writing, approximately 16.06 million cases have been reported worldwide. Like other coronaviruses, SARS-CoV-2 relies on the surface Spike glycoprotein to access the host cells, mainly through the interaction of its Receptor Binding Domain (RBD) with the host receptor Angiotensin-Converting Enzyme2 (ACE2). SARS-CoV-2 infection induces a profound downstream pro-inflammatory cytokine storm. This release of the pro-inflammatory cytokines is underpinning lung tissue damage, respiratory failure, and eventually multiple organ failure in COVID-19 patients. The phosphorylation status of ERK1/2 is positively correlated with virus load and ERK1/2 inhibition suppressed viral replication and viral infectivity. Therefore, molecular entities able to interfere with binding of the SARS-CoV-2 Spike protein to ACE2, or damping hyperinflammatory cytokines storm, blocking ERK1/2 phosphorylation have a great potential to inhibit viral entry along with viral infectivity. Herein, we report that the FDA-approved non-peptide opioid antagonist drug, naltrexone suppresses high fat/LPS induced pro-inflammatory cytokine release both from macrophage cells and Adipose Tissue Macrophage. Moreover, Low Dose Naltrexone (LDN) also showed its activity as an ERK1/2 inhibitor. Notably, virtual docking and simulation data also suggest LDN may disrupt the interaction of ACE2 with RBD. LDN may be considered as a target as the treatment and (or) adjuvant therapy for coronavirus infection. Clinical toxicity measurements may not be required for LDN since naltrexone was previously tested and is an approved drug by the FDA.

Identification of phytocompounds as newer antiviral drugs against COVID-19 through molecular docking and simulation based study

“…Similar to our study, Sen et al [ 31 ], also targeted the same two proteins and screened 10 Indian spices plants for their antiviral activity. Naltrexone, a FDA approved drug was targeted against spike RBD and has shown to bind in the cavity of RBD-ACE2 receptor [ 8 ]. Another study targets both Mpro and RDRP protein and screened phytocompounds against them.…”

“…After energy minimization, the structure was equilibrated through NVT and NPT ensembles for 5ns and 10ns respectively. Finally, MD simulation was performed for 100ns at 300K with 2fs time step using Leap-Frog integrator [ 8 ].…”

Immunometabolic Modulatory Role of Naltrexone in BV-2 Microglia Cells

“…Thus, by abolishing the highly glycolytic mode of the cells preactivated by the potent immunometabolic modulators LPS and IFN-y, naltrexone was shown to be an effective and powerful tool in metabolic reprogramming with promise in the treatment of (neuro)inflammatory conditions. Furthermore, the latest findings in the current field of viral immunology confirm naltrexone as a potential candidate for COVID-19 treatment, as it has the ability to inhibit viral infection at the level of (i) virus entry into the cell due to its molecular entities, being able to interfere with binding of the SARS-CoV-2 spike protein to ACE2, or (ii) damping the hyperinflammatory cytokine storm along with viral infectivity, by confirming its potential in this regard by suppressing LPS-induced cytokine release from pro-inflammatory macrophages [51].…”

Long COVID and its association with neurodegenerative diseases: pathogenesis, neuroimaging, and treatment

“…As a host-targeted broad-spectrum antiviral therapy, naltrexone shows promise in combating COVID-19 infection. Further in vitro and in vivo studies are necessary to determine the efficacy and understand the molecular basis of these compounds’ anti-coronavirus activity or inhibitory potential ( 112 ).…”