期刊
ACS CENTRAL SCIENCE
卷 6, 期 2, 页码 241-246出版社
AMER CHEMICAL SOC
DOI: 10.1021/acscentsci.9b01170
关键词
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资金
- Emmy Noether program of the Deutsche Forschungsgemeinschaft (DFG) [SFB969]
- EU FP7Marie Curie Zukunftskolleg Incoming Fellowship Program
- Fonds der Chemischen Industrie (FCI)
- Konstanz Research School Chemical Biology (KoRS-CB)
We have developed a syringolin-based chemical probe and explored its utility for the profiling of metabolite extracts as potent inhibitors of the 20S proteasome. Activity-guided fractionation by competitive labeling allowed us to isolate and identify glidobactin A and C as well as luminmycin A from a Burkholderiales strain. The natural products exhibited unique subunit specificities for the proteolytic subunits of human and mouse constitutive and immunoproteasome in the lower nanomolar range. In particular, glidobactin C displayed an unprecedented beta 2/beta 5 coinhibition profile with single-digit nanomolar potency in combination with sufficiently high cell permeability. These properties render glidobactin C a promising live cell proteasome inhibitor with potent activity against human breast cancer cell lines and comparably low immunotoxicity.
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