β-Caryophyllene, A Natural Dietary CB2 Receptor Selective Cannabinoid can be a Candidate to Target the Trinity of Infection, Immunity, and Inflammation in COVID-19.

Niraj Kumar Jha,Shreesh Ojha,Sameer N Goyal,Hebaallah Mamdouh Hashiesh,Charu Sharma,Chandragouda R Patil,Hayate Javed,Mf Nagoor Meeran,Seenipandi Arunachalam

doi:10.3389/fphar.2021.590201

Abstract

Coronavirus disease (COVID-19), caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing pandemic and presents a public health emergency. It has affected millions of people and continues to affect more, despite tremendous social preventive measures. Identifying candidate drugs for the prevention and treatment of COVID-19 is crucial. The pathogenesis and the complications with advanced infection mainly involve an immune-inflammatory cascade. Therefore, therapeutic strategy relies on suppressing infectivity and inflammation, along with immune modulation. One of the most promising therapeutic targets for the modulation of immune-inflammatory responses is the endocannabinoid system, particularly the activation of cannabinoid type 2 receptors (CB2R), a G-protein coupled receptor which mediates the anti-inflammatory properties by modulating numerous signaling pathways. To pharmacologically activate the CB2 receptors, a naturally occurring cannabinoid ligand, beta-caryophyllene (BCP), received attention due to its potent anti-inflammatory, antiviral, and immunomodulatory properties. BCP is recognized as a full selective functional agonist on CB2 receptors and produces therapeutic effects by activating CB2 and the nuclear receptors, peroxisome proliferator-activated receptors (PPARs). BCP is regarded as the first dietary cannabinoid with abundant presence across cannabis and non-cannabis plants, including spices and other edible plants. BCP showed tissue protective properties and favorably modulates numerous signaling pathways and inhibits inflammatory mediators, including cytokines, chemokines, adhesion molecules, prostanoids, and eicosanoids. Based on its pharmacological properties, molecular mechanisms, and the therapeutic potential of BCP as an immunomodulator, anti-inflammatory, organ-protective, and antiviral, we hypothesize that BCP could be a promising therapeutic and/or preventive candidate to target the triad of infection, immunity, and inflammation in COVID-19. In line with numerous studies that proposed the potential of cannabinoids in COVID-19, BCP may be a novel candidate compound for pharmaceutical and nutraceutical development due to its unique functional receptor selectivity, wide availability and accessibility, dietary bioavailability, nonpsychoactivity, and negligible toxicity along with druggable properties, including favorable pharmacokinetic and physicochemical properties. Based on reasonable pharmacological mechanisms and therapeutic properties, we speculate that BCP has potential to be investigated against COVID-19 and will inspire further preclinical and clinical studies.

Highlights

COVID-19, a public health emergency and pandemic, has affected millions of people worldwide and continues to do so, despite numerous preventive measures, and this situation will continue until a vaccine is developed (Huang et al, 2020)
Given the role of CB2R activation in attenuating inflammation, viral replication, and favorable modulation of immune systems, BCP endowed with the CB2R selective agonist property has been pharmacologically reasoned to be a candidate for its possible use as preventive agent or therapeutic adjunct in COVID-19
BCP is a unique molecule in various ways, such as being dietary, devoid of psychotropic effects, possessing negligible toxicity, wide availability in plants, oral bioavailability, a druggable property, and functional receptor selectivity

Summary

INTRODUCTION

COVID-19, a public health emergency and pandemic, has affected millions of people worldwide and continues to do so, despite numerous preventive measures, and this situation will continue until a vaccine is developed (Huang et al, 2020). Many of the terpene components present in cannabis are widely consumed in food and used in traditional medicine (Anil et al, 2021) Some of these compounds showed potential to modulate the endocannabinoid system, which represents one of the newest therapeutic targets in regard to regulation of innate and adaptive immunity and immunomodulatory and anti-inflammatory properties. Extract of Cannabis sativa containing phytocannabinoids and terpenes were shown to modulate the inflammatory mediators in alveolar epithelial cells (A549) in COVID-19-associated inflammation and suggested that the phytocannabinoid mix formulation exerted better activity in FIGURE 1 | The structure and various polypharmacological properties and therapeutic potential of BCP. The literature reviewed indicates that BCP may be a promising candidate as a preventive and therapeutic agent or adjuvant for COVID-19 given its pharmacological and molecular mechanisms, including its CB2R agonist property, integrating with its antiviral, anti-inflammatory, and immunomodulatory properties in numerous experimental studies (Sharma et al, 2016). Influenza virus A (IVA) Human Herpes Virus Type 1 (HSV-1) HSV-1 HSV-1 DENV-2, JUNV and HSV-1 Influenza type A (H1N1) HSV-1 DENV-2, JUNV and HSV-1 Human Herpes Virus Type 2 (HSV-2) DENV-2, JUNV and HSV-1 H1N1 HSV-1, HSV-2 HSV-1 HSV-2 HSV-2 Cytopathogenic murine norovirus HSV-1 Real time PCR (H9N2 subtype of AIV)

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