Repurposing HAMI3379 to Block GPR17 and Promote Rodent and Human Oligodendrocyte Differentiation
| Autor: | Evi Kostenis, Jesus Gomeza, Theresa Bödefeld, Anne-Gaelle Letombe, Michel Gillard, Ramona Schrage, Qing Richard Lu, Liguo Zhang, Julia Fischer, Nicole Merten, Klaus Mohr, Ralf Schröder, Katharina Simon, Celine Vermeiren, Oliver Brüstle, Lucas Peters, Stephanie Hennen |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Indoles Cyclohexanecarboxylic Acids Clinical Biochemistry Phthalic Acids Biology Biochemistry Article Receptors G-Protein-Coupled 03 medical and health sciences Mice Structure-Activity Relationship Drug Discovery medicine Animals Humans Remyelination Induced pluripotent stem cell Molecular Biology G protein-coupled receptor Pharmacology Mice Knockout Dose-Response Relationship Drug Molecular Structure Drug discovery Oligodendrocyte differentiation Drug Repositioning Cell Differentiation Oligodendrocyte Cell biology Rats Oligodendroglia 030104 developmental biology medicine.anatomical_structure Knockout mouse Molecular Medicine Signal transduction Propionates |
| Zdroj: | Cell chemical biology. 25(6) |
| ISSN: | 2451-9448 |
| Popis: | Identification of additional uses for existing drugs is a hot topic in drug discovery and a viable alternative to de novo drug development. HAMI3379 is known as an antagonist of the cysteinyl-leukotriene CysLT(2) receptor, and was initially developed to treat cardiovascular and inflammatory disorders. In our study we identified HAMI3379 as an antagonist of the orphan G protein-coupled receptor GPR17. HAMI3379 inhibits signaling of recombinant human, rat, and mouse GPR17 across various cellular backgrounds, and of endogenous GPR17 in primary rodent oligodendrocytes. GPR17 blockade by HAMI3379 enhanced maturation of primary rat and mouse oligodendrocytes, but was without effect in oligodendrocytes from GPR17 knockout mice. In human oligodendrocytes prepared from inducible pluripotent stem cells, GPR17 is expressed and its activation impaired oligodendrocyte differentiation. HAMI3379, conversely, efficiently favored human oligodendrocyte differentiation. We propose that HAMI3379 holds promise for pharmacological exploitation of orphan GPR17 to enhance regenerative strategies for the promotion of remyelination in patients. |
| Databáze: | OpenAIRE |
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