Introduction
Coronavirus disease 2019 (COVID-19) is a major health concern, clinical symptoms of the disease vary from a mild illness, acute respiratory issues to multi-organ failure 1,2. Older age, diabetes, cardiac diseases predict poor prognosis in COVID-19 patients3,4. Although much is known about the mortality of the COVID-19, however, details of the cellular responses to this virus are not known.
Several preclinical and clinical trials data have indicated an elevated cytokine/chemokine response in severe COVID-19 patients and identifies cytokine storm as the most potentially dangerous event for mortality5–7. Several kinases in the MAPK/ERK (mitogen-activated protein kinases/extracellular signal-regulated kinases) pathway are essential for viral replication. ERK1 and ERK2 phosphorylate HIV-1 proteins and enhance viral infectivity8. The phosphorylation status of ERK1/2 is positively correlated with virus load and ERK1/2 inhibition suppressed viral replication and viral infectivity8. Some preclinical findings have suggested targeting ERK1/2 pathway to halt the viral replication and severity of SARS-COV-29.
SARS-CoV-2 uses the homotrimeric spike glycoprotein as the main protein that interacts with the host by binding to host cell receptors (ACE2) to mediate virus invasion for cell entry. Some recent studies have highlighted the important role of ACE2 in mediating entry of SARS-CoV-210,11. A recent report also recognized several critical residues in RBD, including its receptor-binding motif (RBM) that directly contacts with human ACE212. In vitro study using HeLa cells also reinforced the role of ACE2 in mediating entry of SARS-CoV-2, where HeLA cells expressing ACE2 are susceptible to SARS-CoV-2 infection whereas those without ACE2 are not. Furthermore, In vitro binding measurements, experiments showed that the SARS-CoV-2 RBD binds to ACE2 with an affinity in the nanomolar range, indicating that the RBD is a key functional component that is responsible for the binding of SARS-CoV-2 by ACE2 and can be considered as a target for the treatment of coronavirus infection to block SARS-CoV-2 from entering host cells11,12.
There is a very fast ongoing search for therapeutics acting on SARS-CoV-2. Depending on the activity, the therapies can be divided into majorly main categories: (1) Inhibiting the viral RNA synthesis and replication, (2) Deterring the virus from binding to human cell ACE2 receptors, (3) Reinstating the innate immunity, and (4) Blocking the host’s specific receptors or enzymes. Despite many experimental and computational studies currently exploring all of these categories, to date, there is no confirmed effective treatment specifically available for COVID-19.
In this study, we report that the FDA-approved non-peptide opioid antagonist drug13, LDN suppresses high fat/LPS induced pro-inflammatory cytokine release both from macrophage cells and Adipose tissue macrophage (ATM). LDN also showed activity as an ERK1/2 inhibitor. Moreover, virtual docking and simulation data also suggest LDN may disrupt the interaction of ACE2 with RBD. 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 COVID-19 patients, based on our data, we proposed FDA-approved LDN can be used in combination or as an adjuvants therapy to treat mild to moderate symptomatic COVID-19 patients