NASH Target Development Service for Heat Shock Protein 47 (HSP47) Inhibitors

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that affects millions of people and there is no approved therapy yet. The heat shock protein 47 (HSP47) is presenting as the promising target due to the therapeutic potential ability for the treatment of NASH. Creative Biolabs is offering comprehensive target identification for drug discovery and drug development services. With our extraordinary experience in drug discovery programs for HSP47, our scientists are able to help you accelerate your research program and significantly increase your chance of success.

Introduction of HSP47

HSP47, also known as colligin, was originally identified as a collagen-binding protein in mouse embryo parietal endoderm cells, mouse teratocarcinoma stem cells, rat skeletal myoblasts, and chick embryo fibroblasts. This protein belongs to the serine protease inhibitor (serpin) family although it lacks serine protease inhibitory activity. Unlike other serpin family members, HSP47 presents in the endoplasmic reticulum and has only one known client protein, collagen. Collagen is a primary component of the extracellular matrix. Fibrosis can occur when collagen-secreting cells are phenotypically altered to overproduce collagen and other extracellular matrix proteins. HSP47 plays an essential role in collagen biosynthesis by aiding in the assembly of triple helices in procollagen. The evidence is that hsp47 can bind and fold a peptide similar to a partially folded anterior collagen structure. Moreover, HSP47 upregulation has been found in several fibrotic conditions, such as NASH, making it a potential therapeutic target.

Fig.1 Collagen biosynthesis. (HSP47 binds and stabilizes procollagen under the neutral pH in the endoplasmic reticulum) (Sharbeen, 2015)

The Strategy of Antifibrotic Approach for NASH Treatment

Progressive accumulation of fibrosis is the hallmark of NASH disease progression, and therefore, reducing fibrosis is a critical goal of therapy. Fibrosis reflects the net outcome of fibrogenesis and fibrolysis. Both occur concurrently in ongoing liver injury, but over time, fibrogenesis exceeds the liver’s capacity to degrade the accumulated extracellular matrix. Therefore, an antifibrotic approach can either inhibit fibrogenesis and/or promote fibrolysis. To date, some studies have focused on inhibiting fibrogenesis as a target.

HSP47 Inhibitors for NASH Treatment

HSP47 is a chaperone protein that regulates the proper folding of fibrillary collagens. By inhibiting this molecule, collagen is misfolded within the cell and is accumulated rather than secreted, which leads to cell death. Thus, a trial of a liposomal formulation that delivers siRNA silencing expression of HSP47 to enhance stellate cell apoptosis is underway in patients with advanced fibrosis of different etiologies. Besides, a small molecule compound AK778 exhibits the ability to inhibit the interaction of Hsp47 with collagen, its cleavage product Col003 can competitively inhibit the interaction and cause the inhibition of collagen secretion by destabilizing the collagen triple helix. Structural analysis revealed that Col003 competitively binds to the collagen-binding site on Hsp47, and these structural insights could provide a basis for designing more effective therapeutic drugs for managing fibrosis. Thus, Hsp47 could be a potential and promising target for the management of fibrosis in NASH.

Fig.2 Intrahepatic drug targets in phase 2 and 3 clinical trials for NASH. (Friedman, 2018)

Features

• Functional characterization of inhibitors activity
• Strict quality control
• Competitive price
• Short turn-around time

With years of experience and expertise in NASH, Creative Biolabs can provide you the comprehensive services and the highest quality results in the HSP47 inhibitors screening and profiling. With the help of our talented scientists along with the broad services portfolio, we are confident in speeding your project progress and achieving ideal research goals with the most competitive price. For more details and information, please feel free to contact us.

References

1. Sharbeen, G.; et al. HSP47: the new heat shock protein therapeutic target. Heat Shock Protein Inhibitors (pp. 197-219). 2015. Springer, Cham.
2. Friedman, S.L.; et al. Mechanisms of NAFLD development and therapeutic strategies. Nature medicine. 2018, 1.