Targeting Tenascin-C-Toll-like Receptor 4 signalling with Adhiron-derived small molecules - a viable strategy for reducing fibrosis in Systemic Sclerosis

Abstract

Tissue fibrosis is a hallmark of systemic sclerosis (SSc) and results from the excessive production and deposition of collagen and other extracellular matrix proteins by resident fibroblasts. This excessive connective tissue accumulation leads to tissue disruption and subsequent dysfunction in the skin, lungs and other internal organs. Recent studies highlight a role for the matricellular protein Tenascin C in SSc, whereby its stimulation of Toll-like receptor 4 triggers self-sustaining fibroblast activation and ensuing fibrosis. We have utilised Adhiron guided ligand discovery to generate small molecules that target the fibrinogen-like globe domain of Tenascin C, a region involved in Toll-like receptor 4 activation and have demonstrated a reduction in the profibrotic phenotype of human dermal fibroblasts. These studies may facilitate the development of effective targeted therapy for fibrosis in SSc and other fibrotic diseases. Moreover, it highlights the utility of Adhiron guided ligand discovery to generate small molecule inhibitors to selectively modulate proteins. HighlightsO_LIAdhiron screening was undertaken to identify binders to the FBG domain of Tenascin C and the crystal structure of the FBG-Adhiron binding was resolved. C_LIO_LIAdhiron guided ligand discovery was used to generate small molecule inhibitors that selectively target the FBG domain of Tenascin C. C_LIO_LISPR was used to show binding of these molecules to the FBG domain of Tenascin C C_LIO_LIThe small molecule inhibitors generated attenuated TGF{beta}-mediated fibrosis in dermal fibroblasts C_LI