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Published on: September 12, 2019
Targeting Tenascin-C-Toll-like Receptor 4 signalling with Adhiron-derived small molecules - a viable strategy for
Thembaninkosi Gaule1, Katie J Simmons2, Kieran Walker3
1Clinical Population and Sciences Department, Leeds Institute for Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, United Kingdom.
Abstract:
Tissue fibrosis is a hallmark of systemic sclerosis (SSc) and results from the persistent activation of fibroblasts and excessive accumulation of extracellular matrix component such as collagen. Recent evidence implicates the matricellular protein Tenascin-C (TNC) in promoting self-sustaining fibroblast activation and fibrosis via its interaction with Toll-like receptor 4 (TLR4). In this study, we utilized Adhiron-guided ligand discovery to identify small molecule inhibitors targeting the fibrinogen-like globe domain of TNC, a key mediator of TLR4 activation. Two lead compounds (464 and 830) demonstrated structural similarity, favourable ADME profiles, and robust anti-fibrotic activity in vitro. Treatment of dermal fibroblasts derived from SSc patients with either compound significantly reduced Transforming growth factor-β-induced expression of fibrotic genes, ACTA2, COL1A1, COL1A2, and CCN2, and inhibited myofibroblast differentiation. These studies may facilitate the development of effective targeted therapy for fibrosis in SSc and support this novel strategy for small molecule development.
Insights
Researchers identified small molecule inhibitors targeting Tenascin-C (TNC) to treat systemic sclerosis (SSc) fibrosis. These compounds effectively reduced fibrotic gene expression and myofibroblast differentiation in SSc patient cells.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Tissue fibrosis, characterized by excessive extracellular matrix accumulation, is a key feature of systemic sclerosis (SSc).
- Tenascin-C (TNC), a matricellular protein, promotes fibroblast activation and fibrosis through Toll-like receptor 4 (TLR4) signaling.
- Targeting TNC-TLR4 interactions presents a potential therapeutic strategy for SSc fibrosis.
Purpose of the Study:
- To identify small molecule inhibitors targeting the TNC fibrinogen-like globe domain.
- To evaluate the anti-fibrotic activity of these inhibitors in vitro using SSc patient-derived fibroblasts.
Main Methods:
- Adhiron-guided ligand discovery was employed to identify TNC inhibitors.
- Two lead compounds (464 and 830) with favorable ADME profiles were selected.
- In vitro assays assessed the compounds' effects on Transforming growth factor-β-induced fibrotic gene expression and myofibroblast differentiation in SSc dermal fibroblasts.
Main Results:
- Compounds 464 and 830 demonstrated structural similarity and potent anti-fibrotic activity.
- Treatment with these compounds significantly reduced the expression of fibrotic genes (ACTA2, COL1A1, COL1A2, CCN2).
- Myofibroblast differentiation was effectively inhibited by the lead compounds.
Conclusions:
- Small molecule inhibitors targeting TNC show promise for treating SSc fibrosis.
- This study supports a novel strategy for developing targeted therapies for fibrotic diseases.
- Further development of these compounds could lead to effective treatments for systemic sclerosis.
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