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PDBsum entry 6n4t
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Hydrolase/hydrolase inhibitor
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PDB id
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6n4t
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References listed in PDB file
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Key reference
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Title
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Discovery and development of tmprss6 inhibitors modulating hepcidin levels in human hepatocytes.
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Authors
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F.Béliveau,
A.Tarkar,
S.P.Dion,
A.Désilets,
M.G.Ghinet,
P.L.Boudreault,
C.St-Georges,
Ã.‰.Marsault,
D.Paone,
J.Collins,
C.H.Macphee,
N.Campobasso,
A.Groy,
J.Cottom,
M.Ouellette,
A.J.Pope,
R.Leduc.
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Ref.
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Cell Chem Biol, 2019,
26,
1559.
[DOI no: ]
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PubMed id
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Abstract
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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.
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