NASH Target Development Service for Multivesicular Body (MVB) Activators

The two major cellular sites for membrane protein degradation are the proteasome and the lysosome. For lysosomal degradation, ubiquitination triggers the sorting of cargo proteins into the lumen of late endosomal multivesicular bodies (MVBs)/endosomes. Targeting MVB regulators to properly coordinate lysosome-mediated degradation of disease-critical mediators is a promising strategy for NASH treatment. With the extensive experience and the high-end platform and state-of-the-art technology in NASH drug discovery, Creative Biolabs provides our clients high-quality MVB activators and related services to help you get a milestone development in your NASH project.

Introduction of Multivesicular Body (MVB)

Multivesicular bodies (MVBs) are late-stage endosomes in the endocytic pathway characterized by multiple internal vesicles that are enclosed within a single outer membrane. MVBs were initially regarded as purely prelysosomal structures along the degradative endosomal pathway of internalized proteins. They are now known to be involved in a number of endocytic and trafficking functions, including protein sorting, recycling, transport, storage, and release. MVBs and lysosomes are central organelles responsible for the degradation of membrane proteins, where proteins are subjected to a sorting process by the endocytic pathway. Notably, protein degradation, as part of the proteostasis system, has been recognized as an attractive platform for drug targeting, and thus proteolytic-based drugs have been developed as clinical treatments for certain diseases. MVB activators are capable of promoting protein degradation, which makes the MVB-lysosomal pathway a favorable target in the development of proteolytic-based drugs.

Fig.1 Multivesicular body functions. (Hanson, 2012)

Multivesicular Body (MVB) Activators for NASH Treatment

Non-alcoholic steatohepatitis (NASH) is an increasingly prevalent liver pathology that can progress from non-alcoholic fatty liver disease (NAFLD) and is a leading cause of cirrhosis and hepatocellular carcinoma. Defective lysosome-mediated protein degradation is a key process that underlies steatohepatitis and a well-recognized drug target in a variety of diseases. Transmembrane BAX inhibitor motif-containing 1 (TMBIM1) is an effective inhibitor of steatohepatitis and a regulator of the MVB-lysosomal pathway. The expression of TMBIM1 in hepatocytes substantially inhibited high-fat diet-induced insulin resistance, hepatic steatosis, and inflammation in mice. A key factor for the development of NASH is the membrane protein Toll-like receptor 4 (TLR4), whose endocytic transport is coordinated by the MVB-lysosomal pathway. As an MVBregulator, Tmbim1 can promote MVB formation by cooperating with the endosomal sorting complex, thereby promoting lysosomal degradation of TLR4 and inhibiting steatohepatitis and NASH progression. Therefore, targeting MVB activators to control lysosome-mediated protein degradation represents a promising approach for treating NASH.

As a first-class and the undisputed world-leader of drug discovery, Creative Biolabs can offer target identification and validation of MVB activators in clinical and experimental models of NAFLD and NASH. In addition to NASH-related services, we also provide drug design (including Hit to Lead, Lead Optimization, IND-Enabling, Target Identification and Validation, Hit identification) and antibody development services (including Phage Display & Antibody Library Services, Antibody Analysis Services, Antibody Engineering Services) based on other diseases. If you need any services about NASH, please feel free to contact us.

Reference

1. Hanson, P.I.; Cashikar, A. Multivesicular Body Morphogenesis. Annu Rev Cell Dev Biol. 2012, 28(1): 337-362.