Download MendeleyDiscovery and Development of TMPRSS6 Inhibitors Modulating Hepcidin Levels in Human Hepatocytes.
Beliveau, F., Tarkar, A., Dion, S.P., Desilets, A., Ghinet, M.G., Boudreault, P.L., St-Georges, C., Marsault, E., Paone, D., Collins, J., Macphee, C.H., Campobasso, N., Groy, A., Cottom, J., Ouellette, M., Pope, A.J., Leduc, R.(2019) Cell Chem Biol 26: 1559-1572.e9
- PubMed: 31543462
- DOI: https://doi.org/10.1016/j.chembiol.2019.09.004
- Primary Citation of Related Structures:
6N4T - PubMed Abstract:
Iron overload disorders are characterized by the body's inability to regulate iron absorption and its storage which can lead to organ failures. Accumulated evidence has revealed that hepcidin, the master regulator of iron homeostasis, is negatively modulated by TMPRSS6 (matriptase-2), a liver-specific type II transmembrane serine protease (TTSP). Here, we report that treatment with a peptidomimetic inhibitor affecting TMPRSS6 activity increases hepcidin production in hepatic cells. Moreover, similar effects were observed when using non-peptidic inhibitors obtained through optimization of hits from high-throughput screening. Using HepG2 cells and human primary hepatocytes, we show that TMPRSS6 inhibitors block TMPRSS6-dependent hemojuvelin cleavage and increase HAMP expression and levels of secreted hepcidin.
Organizational Affiliation:
Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12(e) Avenue Nord, Sherbrooke, QC J1H 5N4, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada.
