NASH Target Development Service for NLRP3 Inflammasome Inhibitors

Non-alcoholic steatohepatitis (NASH) is the most frequent cause of chronic liver disease and is projected to become the leading etiology of end-stage liver disease requiring liver transplantation by 2020. The causes of inflammation in NASH may be diverse, but activation of a protein scaffold within cells termed the inflammasome NLRP3 has been suggested to play a critical role and is regarded as the promising target for NASH treatment. As a pioneer company of in target identification for drug discovery market, Creative Biolabs has developed extensive platforms for potential target screening to provide our customer with high-quality NASH drug. Our professional scientists will work closely with you to ensure your project a success.

Introduction of NLRP3 Inflammasome

NLRP3 inflammasome is a large intracellular multiprotein complex, which is composed of an inflammasome sensor molecule (typically a NOD-like receptor), and adaptor proteins, such as the apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and the precursor procaspase-1. The inflammasome can recognize a wide range of substances including pathogen-associated molecular patterns (PAMPs), danger associated molecular patterns (DAMPs), and environmental irritants. There are two steps implicated in the activation of the NLRP3 inflammasome. The first step is upregulation of NLRP3 inflammasome components and the procytokines, prointerleukin-1 beta (IL-1β), and pro-IL-18 mediated by Toll-like receptor (TLR). The second step is the assembly of NLRP3 inflammasome complex, which consists of the NOD-like receptor NLRP3, the cytosolic protein ASC, and procaspase-1. NLRP3 inflammasome activation results in the maturation of caspase-1, which further cleaves pro-IL-1β and pro-IL-18 into mature forms and leads to their secretion from the cell. NLRP3 inflammasome is highly expressed in liver and involved in human NASH.

Fig.1 Pathogenic processes in nonalcoholic fatty liver disease. (Greuter, 2017)

NLRP3 Inflammasome Inhibitors

The NLRP3 inflammasome is an intracellular multiprotein complex involved in the production of mature interleukin 1-beta (IL-1β) and inducing metabolic inflammation. Its activation can lead to NASH development and progression, including hepatic steatosis, inflammation, liver injury, and fibrogenesis and may act as a molecular therapeutic target. For example, a small molecule NLRP3 inhibitor, MCC950, was used to treat the NASH in mice model. MCC950 can block the activation of the NLRP3 inflammasome in liver tissue, with resultant suppression of macrophage and neutrophil recruitment. Pharmacological NLRP3 inhibition also reduced hepatic expression of pro-IL-1 and normalized hepatic and circulating IL-1, IL-6 and monocyte chemoattractant protein 1 (MCP-1) levels. Pro-IL-1 and MCP-1 synthesis are modulated by NF-кB, whose nuclear expression was also hampered substantially in these experiments. Hepatic NLRP3 expression was suppressed by MCC950 treatment, most likely because of decreased production of IL-1. Together, these data provide compelling evidence to support NLRP3 inhibitor is a promising strategy for NASH therapeutic.

Fig.2 Activation of NLRP3 inflammasome. (Tschopp, 2010)

Features

• First-class technology platform
• Rapid and comprehensive target screening
• Comprehensive functional testing available
• Competitive and affordable price
• Time- and labor-saving

Creative Biolabs is a well-recognized leader in the disease target discovery and development. We are dedicated to offering high-quality target construction and custom target screening services to meet our clients’ demands precisely. At present, we provide high-quality NLRP3 inflammasome inhibitors for NASH therapy. We also provide other types of inflammasome inhibitors for our worldwide customers to help the diagnosis and treatment of NASH. Please contact us for more information if you are interested in our services and products.

References

1. Greuter, T.; et al. Therapeutic opportunities for alcoholic steatohepatitis and nonalcoholic steatohepatitis: exploiting similarities and differences in pathogenesis. Jci Insight. 2017, 2(17).
2. Tschopp, J.; Schroder, K. NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nature reviews immunology. 2010, 10(3): 210.