The cannabinoid receptor CB2 is highly expressed in immune cells suggesting an important role in numerous diseases such as inflammation, cancer, osteoporosis and liver diseases relating to modulation of the immune system. As a consequence, activation of receptor CB2 is a promising therapeutic strategy for the treatment of a large range of diseases. Indeed, selective CB2 agonists display beneficial anti-inflammatory, anti-cancer and antifibrogenic properties and positive effects on liver disease and osteoporosis. This article reviews the CB2 involvement in the immune system and the promising therapeutical potential of selective CB2 agonists in the treatment of several immune-related diseases.
As long as the structural
study of molecular mechanisms requires
multiple molecular dynamics reflecting contrasted bioactive states,
the subsequent analysis of molecular interaction networks remains
a bottleneck to be fairly treated and requires a user-friendly 3D
view of key interactions. Structural Interaction Network Analysis
Protocols (SINAPs) is a proprietary python tool developed to (i) quickly
solve key interactions able to distinguish two protein states, either
from two sets of molecular dynamics simulations or from two crystallographic
structures, and (ii) render a user-friendly 3D view of these key interactions
through a plugin of UCSF Chimera, one of the most popular open-source
viewing software for biomolecular systems. Through two case studies,
glucose transporter-1 (GLUT-1) and A2A adenosine receptor (A2AR),
SINAPs easily pinpointed key interactions observed experimentally
and relevant for their bioactivities. This very effective tool was
thus applied to identify the amino acids involved in the molecular
enzymatic mechanisms ruling the activation of an immunomodulator drug
candidate, P28 glutathione-S-transferase (P28GST). SINAPs is freely
available at .
Chemical modifications on the NK1 competitive antagonist L-732,138, with a view to creating a dual NK1/NK2 ligand, led to the tryptopban derivative 1 possessing the protected Gly-Leu sequence of the C-terminus of substance P and neurokinin A. Modifications in the nature of the carbamate function increased the selectivity for the NK1 receptor, whereas the inclusion of the indole moiety in fl-carboline or carbazole rings decreased the affinity for both receptors. Free indolylmethyl and Cbz carbamate groups were shown to be essential for NK2 affinity.
The development of more effective, better tolerated drug treatments for progressive pulmonary fibrosis (of which idiopathic pulmonary fibrosis is the most common and severe form) is a research priority. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a key regulator of inflammation and fibrosis and therefore represents a potential therapeutic target. However, the use of synthetic PPAR-γ agonists may be limited by their potentially severe adverse effects. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, we have demonstrated that the non-racemic selective PPAR-γ modulator GED-0507 is able to reduce body weight loss, ameliorate clinical and histological features of pulmonary fibrosis, and increase survival rate without any safety concerns. Here, we focused on the biomolecular effects of GED-0507 on various inflammatory/fibrotic pathways. We demonstrated that preventive and therapeutic administration of GED-0507 reduced the BLM-induced mRNA expression of several markers of fibrosis, including transforming growth factor (TGF)-β, alpha-smooth muscle actin, collagen and fibronectin as well as epithelial-to-mesenchymal transition (EMT) and expression of mucin 5B. The beneficial effect of GED-0507 on pulmonary fibrosis was confirmed in vitro by its ability to control TGFβ-induced myofibroblast activation in the A549 human alveolar epithelial cell line, the MRC-5 lung fibroblast line, and primary human lung fibroblasts. Compared with the US Food and Drug Administration-approved antifibrotic drugs pirfenidone and nintedanib, GED-0507 displayed greater antifibrotic activity by controlling alveolar epithelial cell dysfunction, EMT, and extracellular matrix remodeling. In conclusion, GED-0507 demonstrated potent antifibrotic properties and might be a promising drug candidate for the treatment of pulmonary fibrosis.
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