NASH Target Development Service for Chemokine Antagonists

Chemokines and their receptors play critical roles in inflammatory conditions, which may be a lynchpin in the transition of simple steatosis to non-alcoholic steatohepatitis (NASH). The high-effective chemokines antagonists have gained more attention as a potential target for novel therapeutics in NASH. At Creative Biolabs, we have built multiple powerful platforms, such as Drug discovery, Hit identification, Hit to Lead, Target Identification and Validation, Lead Optimization, for the development of small molecule drugs and finding alternative treatments for different diseases. In particular, we can provide the world's leading strategies and one-stop, custom services to identify new antagonists for patients with NASH.

Introduction of Chemokine

Chemokines, an abbreviation of chemotactic cytokines, are initially termed as secreted factors mediating leukocyte trafficking. They’re small molecular weight proteins of 8-13 kDa and form a family categorized into 4 different groups (C, CC, CXC, CX3C). This classification refers to the structural configuration of two N-terminal conserved cysteines (Cys) motifs. There’re approximately 50 chemokine ligands and 20 cognate chemokine receptors, of which several have been identified as relevant in the context of hepatic diseases.

Tab.1 Relevant chemokines in the pathogenesis of liver diseases and their corresponding receptors. (Marra, 2014)

Chemokine receptors are typical G protein-coupled transmembrane proteins. Multiple ligands bind to a given receptor and, for additional complexity, multiple receptors usually bind a given ligand. Chemokines are best known as protein mediators that cause cytoskeletal rearrangements and control the migration of various cell types, particularly leukocytes, often toward the source or highest concentration of stimulus. They have been shown to be present in many inflammatory and non-inflammatory disease states, including sepsis, arthritis, atherosclerosis, asthma, and cystic fibrosis. Depending on the cell type, chemokines also induce many other types of cellular responses including cell proliferation, survival, development, and immune defense.

Chemokines in the Pathogenesis of NASH

The non-alcoholic fatty liver disease (NAFLD) contains two main subsets: non-alcoholic fatty liver (NAFL), the more common and non-progressive subtype, and NASH, the less common subtype and potentially to the progress of advanced liver damage. Current treatment strategies focus on lifestyle management (weight loss) of modifiable risk factors, and various hypothetical pathogenic mechanisms have been proposed for developing novel molecular drugs with the opportunity to effectively treat NASH patients.

Fig.1 Chemokines in the pathogenesis of fatty liver and non-alcoholic steatohepatitis. (Marra, 2014)

All liver diseases are characterized by an inflammatory response. Sustained liver inflammation is a critical portion of the progression of NASH. Chemokines and their receptors are key players in orchestrating the sequential influx of immune cells into injured organs, driving inflammatory responses to specific triggers. Liver inflammation is regulated by chemokines, which cause the migration and activity of hepatocytes, hepatic stellate cells, Kupffer cells, endothelial cells, and circulating immune cells. The effects of different chemokines and corresponding receptors vary during the pathogenesis of distinct liver diseases. During the development of NASH diseases, CCL2 and its receptor are upregulated in the livers, where they promote macrophage accumulation, inflammation, steatosis, and fibrosis, as well as in adipose tissue (AT). Thereby, CCL2 signaling pathway links hepatic and systemic inflammation associated with insulin resistance and metabolic disorders. Through chemokines’ role in the pathogenesis of liver diseases, their valuable use as biomarkers or therapeutic targets has been considered in antagonists research.

Chemokine Antagonist Developments at Creative Biolabs

The drugs currently taken by NASH patients are aimed at the accompanying characteristics of metabolic syndrome, such as diabetes, hypertension, and dyslipidemia. For selected patients with NASH, agents like Vitamin E and pioglitazone are recommended with caveats, but still have concerns of side-effect profile.

Numerous clinical trials are ongoing, making use of experimental drugs and molecules targeting specific mechanistic pathways to efficaciously treat NASH. Several pathways targeted by pharmacologic agents involve chemokine receptor and antagonism. At Creative Biolabs, we would like to introduce our versatile, flexible, and powerful platforms for varieties of chemokine antagonist development services. The hotspots of chemokine and their receptors include but not limited to:

Notably, our high-end target screening services display the following advantages.

If you have any other request regarding NASH-related services, please feel free to contact us or directly send us an inquiry.

References

1. Shapiro H.; et al. Bile acids in glucose metabolism in health and disease. Journal of Experimental Medicine. 2018, 215(2): 383-396.
2. Marra, F.; et al. Roles for chemokines in liver disease. Gastroenterology. 2014, 147(3): 577-594.