Naltrexone a potential therapeutic candidate for COVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has recently emerged as a new public health threat. SARS-CoV-2 is the cause of coronavirus disease (COVID-19) that has resulted in a global pandemic. At the time of writing, approximately 6.6 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 proinflammatory cytokine storm. This release of the proinflammatory 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 FDAapproved non-peptide opioid antagonist drug, naltrexone suppresses high fat/LPS induced pro-inflammatory cytokine release both from macrophage cells and Adipose Tissue Macrophage (ATM). 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 and thus LDN may be considered as a target as the treatment and (or) adjuvant therapy for coronavirus infection.

Opioid use disorder and health service utilization among COVID-19 patients in the US: A nationwide cohort from the Cerner Real-World Data

“…Compared to patients without an OUD, COVID-19 patients with OUD who were treated with naltrexone demonstrated even higher risk for hospitalization, length of stay, and invasive ventilator dependence, but not death. Naltrexone has been proposed as a possible therapeutic candidate for COVID-19 due to its ability to act as a host-targeted broad-spectrum antiviral therapy [26]; however, the small sample of patients treated with naltrexone in this study do not show clear mortality advantages but do show more intensive health service use. COVID-19 patients with OUDs who do not have charts indicating medication treatment exhibit greater risk for all health service outcomes and greater mortality compared to their counterparts without an OUD.…”

Targeting Epstein‐Barr Virus dUTPase, an Immunomodulatory Protein Using Antiviral, Anti‐Inflammatory, and Neuroprotective Phytochemicals

“…RMSD is one of the commonly used quantitative measures to assess the stability of the docked complexes [34–36] . It calculates the difference between the protein backbone from its initial position to its final conformation.…”

Therapeutic potential of long-acting opioids and opioid antagonists for SARS-CoV-2 infection

“… 15 Moreover, in vitro, naltrexone suppressed production of pro-inflammatory cytokines, and in docking simulation studies disrupted interaction between ACE-2 and the receptor binding domain of the SARS-CoV-2 virus spike protein, leading to a proposal to repurpose low dose naltrexone to treat patients with COVID-19. 16 …”

“… Opioids and opioid antagonists interact with the ACE-2 trans-membrane protein, a molecule that is widely considered to be main host cell receptor for SARS-CoV-2 cell entry. 14 , 16 , 17 5. Opioids interact with the membrane receptor TLR4, a component of the innate immune system implicated in the pathogenesis of SARS-CoV-2.…”

“… In vitro and in silico s tudies aimed at repurposing drugs for treatment of COVID-19 have identified that opioids have therapeutic potential. 14 , 15 , 16 , 23 7. The opioid drugs morphine, codeine, tramadol, and the opioid antagonist naltrexone have been proposed for the treatment of COVID-19.…”