Details
| Originalsprache | Englisch |
|---|---|
| Aufsatznummer | e0201605 |
| Fachzeitschrift | PLOS ONE |
| Jahrgang | 13 |
| Ausgabenummer | 7 |
| Publikationsstatus | Veröffentlicht - 31 Juli 2018 |
| Extern publiziert | Ja |
Abstract
The identification of inhibitors of eukaryotic protein biosynthesis, which are targeting single translation factors, is highly demanded. Here we report on a small molecule inhibitor, gephyronic acid, isolated from the myxobacterium Archangium gephyra that inhibits growth of transformed mammalian cell lines in the nM range. In direct comparison, primary human fibroblasts were shown to be less sensitive to toxic effects of gephyronic acid than cancer-derived cells. Gephyronic acid is targeting the protein translation system. Experiments with IRES dual luciferase reporter assays identified it as an inhibitor of the translation initiation. DARTs approaches, co-localization studies and pull-down assays indicate that the binding partner could be the eukaryotic initiation factor 2 subunit alpha (eIF2α). Gephyronic acid seems to have a different mode of action than the structurally related polyketides tedanolide, myriaporone, and pederin and is a valuable tool for investigating the eukaryotic translation system. Because cancer derived cells were found to be especially sensitive, gephyronic acid could potentially find use as a drug candidate.
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in: PLOS ONE, Jahrgang 13, Nr. 7, e0201605, 31.07.2018.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review
}
TY - JOUR
T1 - Investigations on the mode of action of gephyronic acid, an inhibitor of eukaryotic protein translation from myxobacteria
AU - Muthukumar, Yazh
AU - Münkemer, Johanna
AU - Mathieu, Daniel
AU - Richter, Christian
AU - Schwalbe, Harald
AU - Steinmetz, Heinrich
AU - Kessler, Wolfgang
AU - Reichelt, Joachim
AU - Beutling, Ulrike
AU - Frank, Ronald
AU - Büssow, Konrad
AU - van den Heuvel, Joop
AU - Brönstrup, Mark
AU - Taylor, Richard E.
AU - Laschat, Sabine
AU - Sasse, Florenz
N1 - Funding information: This work was supported by Deutsche Forschungsgemeinschaft (http://www.dfg.de/) grants SA 356/7-1 to FS and LA 13-1 to SL. We thank Prof. Daniel Romo, Department of Chemistry and Biochemistry, Baylor University, Waco, TX, for a generous gift of DMDA-pateamine A, the HZI Graduate School for support by an excellent scientist training programme, Dr. Mario Köster, HZI, for providing us the bicistronic polio IRES plasmid, Bettina Hinkelmann and Wera Collisi, HZI, for skilful technical assistance.
PY - 2018/7/31
Y1 - 2018/7/31
N2 - The identification of inhibitors of eukaryotic protein biosynthesis, which are targeting single translation factors, is highly demanded. Here we report on a small molecule inhibitor, gephyronic acid, isolated from the myxobacterium Archangium gephyra that inhibits growth of transformed mammalian cell lines in the nM range. In direct comparison, primary human fibroblasts were shown to be less sensitive to toxic effects of gephyronic acid than cancer-derived cells. Gephyronic acid is targeting the protein translation system. Experiments with IRES dual luciferase reporter assays identified it as an inhibitor of the translation initiation. DARTs approaches, co-localization studies and pull-down assays indicate that the binding partner could be the eukaryotic initiation factor 2 subunit alpha (eIF2α). Gephyronic acid seems to have a different mode of action than the structurally related polyketides tedanolide, myriaporone, and pederin and is a valuable tool for investigating the eukaryotic translation system. Because cancer derived cells were found to be especially sensitive, gephyronic acid could potentially find use as a drug candidate.
AB - The identification of inhibitors of eukaryotic protein biosynthesis, which are targeting single translation factors, is highly demanded. Here we report on a small molecule inhibitor, gephyronic acid, isolated from the myxobacterium Archangium gephyra that inhibits growth of transformed mammalian cell lines in the nM range. In direct comparison, primary human fibroblasts were shown to be less sensitive to toxic effects of gephyronic acid than cancer-derived cells. Gephyronic acid is targeting the protein translation system. Experiments with IRES dual luciferase reporter assays identified it as an inhibitor of the translation initiation. DARTs approaches, co-localization studies and pull-down assays indicate that the binding partner could be the eukaryotic initiation factor 2 subunit alpha (eIF2α). Gephyronic acid seems to have a different mode of action than the structurally related polyketides tedanolide, myriaporone, and pederin and is a valuable tool for investigating the eukaryotic translation system. Because cancer derived cells were found to be especially sensitive, gephyronic acid could potentially find use as a drug candidate.
UR - http://www.scopus.com/inward/record.url?scp=85050817741&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0201605
DO - 10.1371/journal.pone.0201605
M3 - Article
C2 - 30063768
AN - SCOPUS:85050817741
VL - 13
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 7
M1 - e0201605
ER -