Cannabinoid Type-2 Receptor Agonist, JWH133 May Be a Possible Candidate for Targeting Infection, Inflammation, and Immunity in COVID-19

Abhijit Dey,Vivek Dhar Dwivedi,Niraj Kumar Jha,Kavindra Kumar Kesari,Shreesh Ojha,Mohamed Fizur Nagoor Meeran,Piyush Kumar Gupta,Saurabh Kumar Jha,Charu Sharma

doi:10.3390/immuno1030020

Abhijit Dey, Vivek Dhar Dwivedi + Show 7 more

Open Access

https://doi.org/10.3390/immuno1030020

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Abstract

The COVID-19 pandemic, caused by SARS-CoV-2, is a deadly disease affecting millions due to the non-availability of drugs and vaccines. The majority of COVID-19 drugs have been repurposed based on antiviral, immunomodulatory, and antibiotic potential. The pathogenesis and advanced complications with infection involve the immune-inflammatory cascade. Therefore, a therapeutic strategy could reduce infectivity, inflammation, and immune modulation. In recent years, modulating the endocannabinoid system, particularly activation of the cannabinoid type 2 (CB2) receptor is a promising therapeutic target for modulation of immune-inflammatory responses. JWH133, a selective, full functional agonist of the CB2 receptor, has been extensively studied for its potent anti-inflammatory, antiviral, and immunomodulatory properties. JWH133 modulates numerous signaling pathways and inhibits inflammatory mediators, including cytokines, chemokines, adhesion molecules, prostanoids, and eicosanoids. In this study, we propose that JWH133 could be a promising candidate for targeting infection, immunity, and inflammation in COVID-19, due to its pharmacological and molecular mechanisms in numerous preclinical efficacy and safety studies, along with its immunomodulatory, anti-inflammatory, organoprotective, and antiviral properties. Thus, JWH133 should be investigated in preclinical and clinical studies for its potential as an agent or adjuvant with other agents for its effect on viremia, infectivity, immune modulation, resolution of inflammation, reduction in severity, and progression of complications in COVID-19. JWH133 is devoid of psychotropic effects due to CB2 receptor selectivity, has negligible toxicity, good bioavailability and druggable properties, including pharmacokinetic and physicochemical effects. We believe that JWH133 could be a promising drug and may inspire further studies for an evidence-based approach against COVID-19.

Highlights

Coronavirus disease-2019 (COVID-19), a pandemic and public health emergency caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a deadly disease that is affecting millions of people all over the world because of the non-availability of specific drugs or vaccines [1]
CB2R activation in attenuating inflammation, viral replication and favorably modulating immune systems, it has been speculated that JWH133 endowed with cannabinoid type 2 (CB2) selective agonist property and showing affinity to Mpro may be a candidate for further investigation for its possible use in management of COVID-19
The potent anti-inflammatory activity involves multiple pathways, including inhibition of proinflammatory cytokines, chemokines, and adhesion molecules, along with suppression of macrophage infiltration and neutrophil-endothelial cell interactions that inhibit a cytokine storm, which is a major reason for death in patients with COVID-19

Summary

Introduction

Coronavirus disease-2019 (COVID-19), a pandemic and public health emergency caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a deadly disease that is affecting millions of people all over the world because of the non-availability of specific drugs or vaccines [1]. These drugs have the potential to either block the virus from entering host cells or prevent viral replication, and attenuate hyperimmune and hyperinflammatory states to prevent the disease progression and complications [3] The utilization of these drugs in COVID-19 is mostly empirical, based on clinical experience of their therapeutic benefits in the management of previous SARS, Middle East respiratory syndrome, and Ebola virus epidemics. We perform molecular docking studies on JWH133 for the viral and host targets and found that Mpro appear to be a one of the important targets, we elaborated the potential of JWH133 in SARS-CoV-2 infection integrating with previous findings, regarding its immunomodulatory, anti-inflammatory, and antiviral properties

Molecular Docking of JWH133 for its Activity on Mpro

Proposed

CB2 Receptors Mediated Immunomodulatory Activity of JWH133

CB2 Receptors Mediated

CB2 Receptors Mediated Anti-Inflammatory and Antiviral Activity of JWH133

Limitations on the Proposed Therapeutic Applications of JWH133

Findings

Conclusions