key: cord-0742307-plj76rhy
authors: Nagoor Meeran, M. F.; Sharma, Charu; Goyal, Sameer N.; Kumar, Sanjay; Ojha, Shreesh
title: CB2 receptor‐selective agonists as candidates for targeting infection, inflammation, and immunity in SARS‐CoV‐2 infections
date: 2020-11-15
journal: Drug Dev Res
DOI: 10.1002/ddr.21752
sha: a37602fd9f36dc1ef34099b9868d78813450e02a
doc_id: 742307
cord_uid: plj76rhy

The COVID‐19 pandemic caused by SARS‐CoV‐2 is a deadly disease afflicting millions. The pandemic continues affecting population due to nonavailability of drugs and vaccines. The pathogenesis and complications of infection mainly involve hyperimmune‐inflammatory responses. Thus, therapeutic strategies rely on repurposing of drugs aimed at reducing infectivity and inflammation and modulate immunity favourably. Among, numerous therapeutic targets, the endocannabinoid system, particularly activation of cannabinoid type‐2 receptors (CB2R) emerged as an important one to suppress the hyperimmune‐inflammatory responses. Recently, potent antiinflammatory, antiviral and immunomodulatory properties of CB2R selective ligands of endogenous, plant, and synthetic origin were showed mediating CB2R selective functional agonism. CB2R activation appears to regulate numerous signaling pathways to control immune‐inflammatory mediators including cytokines, chemokines, adhesion molecules, prostanoids, and eicosanoids. Many CB2R ligands also exhibit off‐target effects mediating activation of PPARs, opioids, and TRPV, suggestive of adjuvant use with existing drugs that may maximize efficacy synergistically and minimize therapeutic doses to limit adverse/ side effects. We hypothesize that CB2R agonists, due to immunomodulatory, antiinflammatory, and antiviral properties may show activity against COVID‐19. Based on the organoprotective potential, relative safety, lack of psychotropic effects, and druggable properties, CB2R selective ligands might make available promising candidates for further investigation.

inflammation in COVID-19. CB2R, mainly expressed in immune cells, participate in the inflammatory process by regulating proinflammatory mediators, including cytokines, chemokines, adhesion molecules, and the polarization of macrophages. The latter is a key regulator of proinflammatory (M1)/antiinflammatory (M2) pathways.

CB2R primarily couples to Gi upon activation resulting in inhibition of an adenylyl cyclase agonist and further activates 5 0 -AMPactivated protein kinase (AMPK) pathways. These actions result in reduced anabolic reactions, and in turn, promote oxidative phosphorylation and exert antiinflammatory effects (Stasiulewicz et al., 2020; van Niekerk et al., 2019) . Macrophages present in human lung expresses CB2R, and upon activation, significantly inhibits the onset of cytokine storm by suppressing proinflammatory cytokines, chemokines, growth factors, and adhesion molecules (Staiano et al., 2016) . Activation of CB2R produces antiinflammation by inhibiting recruitment of leukocytes, reducing synthesis and release of chemokines, adhesion molecules, prostanoids, eicosanoids, reactive oxygen species, and proinflammatory cytokines (Stasiulewicz et al., 2020) . Proinflammatory cytokine expression, including IL-1β, TNF-α, and particularly a massive rise in IL-6, reflect the severity of pathology, prognosis, and mortality in acute lung injury associated with COVID-19 infection. Inhibition of IL-6 production mitigates acute lung injuries (Bohn et al., 2020) . Further, activation of inflammasomes are also triggers of the cytokine storm and participate in clinical and pathological manifestations of COVID-19 (Tay et al., 2020) .

Additionally, CB2 gene (CNR2) polymorphism shown to play a role in the immunopathogenesis associated with severe necroinflammation in patients with respiratory syncytial virus (Tahamtan et al., 2018) , chronic hepatitis C (Coppola et al., 2014) , childhood immune thrombocytopenic purpura , and neuroinflammation in HIV/HCV co-infected patients (Sagnelli et al., 2017) . CB2R knockout mice showed increased susceptibility and vulnerability to influenza infection demonstrated the importance of CB2R in immunoregulation in respiratory viral infections (Kapellos et al., 2019) . The activation of CB2R is reported to suppress lung pathology in infants infected with acute respiratory syncytial virus by reducing cytokines and chemokines (Tahamtan et al., 2018) . In HIV patients, CB2R activation suppresses infectivity, transmission and replication of the virus in monocytes and macrophages (Ramirez et al., 2013) .

CB2R activation shows protection against acute lung injury, druginduced lung injuries, airway hyperresponsiveness, cough centers, pulmonary inflammation, and fibrosis, by correcting lung permeability, leukocyte trafficking, and preserving tight junctions (Pacher & Mechoulam, 2011) . Further, at the doses at which cannabinoids produce bronchodilation, CB2R activation did not elicit central respiratory depression. Some patients that recover from COVID-19 are reported to develop persistent lung dysfunction and fibrosis, initiated by microinjury, inflammation, and fibroblast activation (Bohn et al., 2020) . hypoxia, and overexpression of tissue factors following the cytokine storm, also referred to as capillary leak syndrome in reference to thrombosis (Bohn et al., 2020; Tay et al., 2020) . CB2R expressed in hematopoietic and endothelial cells upon activation attenuates inflammatory responses including endothelial activation, immune cell adhesion, and migration and protected against inflammation by increasing transendothelial resistance, tight junction, and inhibiting inflammatory mediators including adhesion molecules (Pacher & Mechoulam, 2011) .

Liver injury/dysfunction in COVID-19 patients is a common complication due to the virus itself or other concurrent complications, such as hepatotoxicity of drugs, mainly antipyretics or immunomodulators, currently used in COVID-19 management. Preexisting chronic liver disease is an indicator of poorer prognosis (Feng et al., 2020) .

CB2 gene polymorphism with indices of liver damage in obese children suggests a hepatoprotective role of CB2R .

CB2R activation ameliorated portal hypertension, the severity of portosystemic collaterals and mesenteric angiogenesis, intrahepatic angiogenesis, and fibrosis in cirrhotic rats. CB2R activation was showed hepatoprotective against acute liver injury or failure, septic liver, liver cirrhosis, and hepatic ischemia-reperfusion injury, fibrosis, steatosis as well as ascites and peritonitis.

Acute kidney injury includes direct viral-induced tubular and glomerular injury, sepsis-associated injury, and thrombotic disease (Farouk, Fiaccadori, Cravedi, & Campbell, 2020) . CB2R activation salvages kidneys in acute renal injury by inhibiting proinflammatory cytokines, chemokines, and apoptosis. Intestinal inflammation and diarrhea also, occur as complications in COVID-19 patients. A reduction of mucosal ACE2 following virus entry, resulting in altered elevated angiotensin levels, increased TNF-α and tryptophan deficiency (Taxonera et al., 2020) . CB2R activation showed to correct motility impairment, intestinal secretion and integrity, neurogenic intestinal inflammation, intestinal I/R injury and attenuation of intestinal inflammation by enhancing apoptosis in activated T cells, F I G U R E 1 The proposed possible mechanisms andpotential of CBR2 agonists in SARS-CoV2 infection Riera, Song, Roberts, & Hontecillas, 2010; Du, Ma, Liu, Yan, & Tang, 2017; Skolnik, Rabbi, Mathys, & Greenberg, 2002) . These off target effects of CB2R activation could be additionally effective in ameliorating pulmonary inflammation via inhibiting the generation of proinflammatory cytokines, collagen secretion, apoptosis of alveolar type II epithelial cells, and promoting surfactant-associated protein A expression (Huang et al., 2019) . The beneficial effects of CB2R activation and associated off-target effects in models of endotoxemia, sepsis, allergic airway inflammation and acute lung injury, and acute respiratory distress syndrome suggest that cannabinoid ligands targeting CB2R may be novel candidates targeting the trinity of COVID-19; infection, immunity, and inflammation ( Figure 1 ).

Much information presented is solely based on reports from previously published studies on immunomodulatory, anti-inflammatory, and antimicrobial potential of CB2R agonists. Synthesis of CB2R ligands and preclinical and clinical studies for their efficacy are promising in numerous related pathogenesis, thus the CB2R selective ligands can be evaluated in experimental models of COVID-19. However, a reliable preclinical SARS-CoV-2-infected animal model is not available for preclinical evaluations. The potent pleiotropic properties of CB2R ligands could be leveraged as effective compounds in supportive treatment of COVID-19 infection.

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The authors are grateful for providing research facilities and research grant supports from the United Arab Emirates University, Al Ain, UAE.

The authors declare no conflicts of interest.

The present manuscript is a perspective/commentary based on the published reports. The information and data presented in this manuscript are appropriately cited in the manuscript.

https://orcid.org/0000-0001-7801-2966