Meprin β is specifically inhibited by its cognate synthetic propeptide
8 affiliations
- 1Biochemical Institute, Unit for Degradomics of the Protease Web, Kiel University, Otto-Hahn-Platz 9, Kiel, 24118, Germany.
- 2Dept. of Immunology and Regenerative Biology, Weizmann Institute of Science, Max and Lillian Candiotty Building, Room 207, 234 Herzl St. Rehovot, Rehovot, 76100, Israel.
- 3Department of Agricultural Development, Agri-food & Management of Natural Resources, National and Kapodistrian University of Athens, Evripos Campus, Psachna, Evia, 34400, Greece.
- 4Institute of Pathobiochemistry, University Medical Center Mainz, Mainz, Germany.
- 5Tissue Biology and Therapeutic Engineering Laboratory (LBTI-UMR 5305 CNRS), Lyon University, Lyon, France.
- 6Molecular Neurodegeneration, Institute of Pathobiochemistry, University Medical Center Mainz, Mainz, Germany.
- 7Dept. of Immunology and Regenerative Biology, Weizmann Institute of Science, Max and Lillian Candiotty Building, Room 207, 234 Herzl St. Rehovot, Rehovot, 76100, Israel. [email protected].
- 8Biochemical Institute, Unit for Degradomics of the Protease Web, Kiel University, Otto-Hahn-Platz 9, Kiel, 24118, Germany. [email protected].
Abstract
Meprin β is a zinc-dependent metalloprotease of the astacin family highly expressed in kidney and intestine. Dysregulation of meprin β expression and activity was observed in several pathological conditions such as Alzheimer’s disease, cancer, fibrosis, and inflammatory bowel disease. Therefore, inhibition of meprin β could be a promising therapeutic option to treat pathological conditions influenced by this protease. However, available small-molecule compounds such as the broad-spectrum metalloproteinases inhibitors marimastat or actinonin lack specificity. Hence, more selective meprin β inhibitors needs to be developed. Here, we provide evidence that the synthetically generated cognate meprin β propeptide serves as highly specific inhibitor for the protease (IC 50 = 1.35 µM), while other related metalloproteases such as meprin α and a disintegrin and metalloproteinases (ADAMs) are not affected. Employing a targeted approach revealed that removal of the last four C-terminal amino acids of the propeptide significantly improved its inhibitory capacity (IC 50 = 0.68 µM). In cell-based experiments, treatment with the propeptide resulted in diminished meprin β activity and decreased cleavage of its substrates, including the interleukin-6 receptor (IL-6R) and the G protein-coupled receptor latrophilin-3 (LPHN3). Suitability was further confirmed in ex vivo cultivated organotypic brain slices, where the administration of the propeptide also resulted in decreased meprin β activity and diminished latrophilin-3 cleavage. Thus, not only the synthetic wildtype propeptide but especially a C-terminally truncated propeptide of meprin β represent highly specific inhibitors with potential for therapeutic application.
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BibTeX
@article{armbrust2026meprin,
title = {{Meprin β is specifically inhibited by its cognate synthetic propeptide}},
author = {Fred Armbrust and Hannah Bruhn and Kira Bickenbach and Nicolas Steen and Sapir Shcoory and Nikolaos Afratis and Nele Korn and Hagen Körschgen and Catherine Moali and Claus U Pietrzik and Irit Sagi and Christoph Becker-Pauly},
journal = {Cellular and Molecular Life Sciences},
year = {2026},
month = jul,
doi = {10.1007/s00018-026-06361-4},
url = {https://hal.science/hal-05762009v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Meprin β is specifically inhibited by its cognate synthetic propeptide
AU - Fred Armbrust
AU - Hannah Bruhn
AU - Kira Bickenbach
AU - Nicolas Steen
AU - Sapir Shcoory
AU - Nikolaos Afratis
AU - Nele Korn
AU - Hagen Körschgen
AU - Catherine Moali
AU - Claus U Pietrzik
AU - Irit Sagi
AU - Christoph Becker-Pauly
PY - 2026
DA - 2026/07/01
JO - Cellular and Molecular Life Sciences
DO - 10.1007/s00018-026-06361-4
UR - https://hal.science/hal-05762009v1
AB - Meprin β is a zinc-dependent metalloprotease of the astacin family highly expressed in kidney and intestine. Dysregulation of meprin β expression and activity was observed in several pathological conditions such as Alzheimer’s disease, cancer, fibrosis, and inflammatory bowel disease. Therefore, inhibition of meprin β could be a promising therapeutic option to treat pathological conditions influenced by this protease. However, available small-molecule compounds such as the broad-spectrum metalloproteinases inhibitors marimastat or actinonin lack specificity. Hence, more selective meprin β inhibitors needs to be developed. Here, we provide evidence that the synthetically generated cognate meprin β propeptide serves as highly specific inhibitor for the protease (IC 50 = 1.35 µM), while other related metalloproteases such as meprin α and a disintegrin and metalloproteinases (ADAMs) are not affected. Employing a targeted approach revealed that removal of the last four C-terminal amino acids of the propeptide significantly improved its inhibitory capacity (IC 50 = 0.68 µM). In cell-based experiments, treatment with the propeptide resulted in diminished meprin β activity and decreased cleavage of its substrates, including the interleukin-6 receptor (IL-6R) and the G protein-coupled receptor latrophilin-3 (LPHN3). Suitability was further confirmed in ex vivo cultivated organotypic brain slices, where the administration of the propeptide also resulted in decreased meprin β activity and diminished latrophilin-3 cleavage. Thus, not only the synthetic wildtype propeptide but especially a C-terminally truncated propeptide of meprin β represent highly specific inhibitors with potential for therapeutic application.
SN - 1420-682X
SN - 1420-9071
ER -