NASH Target Development Service for CCL2-CCR2

Murine models of non-alcoholic steatohepatitis (NASH) have clearly manifested that the infiltration of monocytes is a crucial pathogenic event promoting steatohepatitis and fibrosis progression. Monocytes are primarily recruited by CCL2-CCR2 interactions in NASH. Based on rich experience and advanced equipment, Creative Biolabs can provide high-end small molecular discovery, screening, and optimization services for CCL2-CCR2 antagonists so that these molecules can be translated into novel treatment options for patients with NASH, even other liver diseases.

Introduction of CCL2-CCR2

Chemokines are a family of soluble proteins that regulate cell migration via the formation of concentration gradients. CCL2 (C-C motif chemokine ligand 2), also known as monocyte chemoattractant protein 1 (MCP1) or small inducible cytokine A2, is a small cytokine that belongs to the C-C class of chemokine family. It is a key modulator of inflammation, manipulating macrophage recruitment during infections, wound healing, and autoimmune diseases. CCR2 (C-C chemokine receptor type 2), also known as cluster of differentiation 192 (CD192), is a chemokine receptor principally expressed on monocytes that might be a pivotal receptor in mediating their tissue influx upon immune-based inflammation. This factor is a G protein-coupled receptor (GPCR), the ligands for which include CCL2, CCL7, CCL8, etc.

CCL2 exhibits a particular affinity for CCR2 receptor, and signaling through CCR2 leads to activation of downstream pathways involving p42/44MAPK, phospholipase C-γ, and protein kinase C (PKC) to modulate cell adhesion and motility in macrophages. Furthermore, the important role of CCL2-CCR2 as a modulator of tissue influx of monocytes has been exhibited in studies of mice engineered to be deficient in either CCL2 or CCR2.

Fig.1 The structure of CCL2, CCR2.

The Inhibition of CCL2-CCR2 in NASH

Sustained hepatic inflammation is a vital factor in the progression of chronic liver diseases, including NASH and hepatitis C. NASH is a subtype of non-alcoholic fatty liver disease (NAFLD) and there’s no approved pharmacotherapy yet. While lifestyle modifications remain the mainstay of treatment, more alternative choices for NASH are required.

The CCL2-CCR2 pathway is especially activated in patients with NASH. CCL2 as the primary ligand for CCR2 has been found to be increased in the liver of NASH patients and experimental mouse models of steatohepatitis and subsequent fibrosis. As reports, monocyte/macrophage infiltration into the liver in the context of injury is critically regulated by CCL2-CCR2 axis and is functionally significant for perpetuating hepatic inflammation and fibrogenesis. mNOX-E36, a structured L-enantiomeric RNA oligonucleotide (Spiegelmer), can potently bind and inhibit murine CCL2. Hepatic monocyte/macrophage infiltration can be efficiently and specifically blocked by mNOX-E36 (murine CCL2-specific antagonist) in two independent murine models of chronic liver injury. The relevant ameliorated steatosis development suggested that inhibition of CCL2 is an appealing approach for pharmacological treatment in hepatic inflammation and steatohepatitis.

Fig.2 Important chemokine pathways for the initiation of liver inflammation. (Marra, 2014)

Antagonist Developments at Creative Biolabs

Liver macrophages consist of distinct populations termed Kupffer cells and monocyte-derived macrophages. Liver injury triggers the activation of Kupffer cell, resulting in inflammatory cytokine and chemokine release. The interventions regulating Kupffer cell activation, monocyte recruitment (e.g. via inhibiting chemokines like CCL2 or CCR2) or macrophage polarization and differentiation could promote tissue repair and regression of fibrosis. At Creative Biolabs, we’re skilled at offering small molecule drug development platforms to identify new CCL2-CCR2 chemokine antagonists. Meanwhile, we also could provide custom target screening services for other chemokines.

As a first-class service supplier in the world, Creative Biolabs has achieved numerous projects regarding disease target development and therapeutic antibody production to satisfy clients’ needs precisely. Besides, we have several high-quality antibody development platforms, such as Phage Display & Antibody Library Services, Antibody Analysis Services, Antibody Engineering Services. If you have any issue with our services, please feel free to contact us.

Reference

1. Marra, F.; et al. Roles for chemokines in liver disease. Gastroenterology. 2014, 147(3): 577-594.