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Activity Enhancement of the Synthetic Syrbactin Proteasome Inhibitor Hybrid and Biological Evaluation in Tumor Cells

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2012
Author Archer CR, Groll M, Stein ML, Schellenberg B, Clerc J, Kaiser M, Kondratyuk TP, Pezzuto JM, Dudler R, Bachmann AS,
Project Structure, function and biosynthesis of syrbactins
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Original article (peer-reviewed)

Volume (Issue) 51(34)
Page(s) 6880 - 6888
Title of proceedings BIOCHEMISTRY


Syrbactins belong to a recently emerged class of bacterial natural product inhibitors that irreversibly inhibit the proteasome of eukaryotes by a novel mechanism. The total syntheses of the syrbactin molecules syringolin A, syringolin B, and glidobactin A have been achieved which enabled the preparation of syrbactin-inspired derivatives, such as the syringolin A/glidobactin A hybrid molecule SylA-GlbA. To determine the potency of SylA-GlbA, we employed both in vitro and cell culture-based proteasome assays that measure the sub-catalytic chymotrypsin-like (CT-L), trypsin-like (T-L), and caspase-like (C-L) activities. We further studied the inhibitory effects of SylA-GlbA on tumor cell growth, using a panel of multiple myeloma, neuroblastoma, and ovarian cancer cell lines and showed that SylA-GlbA strongly blocks the activity of NF-κB. To gain more insights into the structure-activity relationship, we co-crystallized the SylA-GlbA compound in complex with the proteasome and determined the X-ray structure. The electron density map displays covalent binding of the Thr-1Oγ of all active sites to the macrolactam ring of the ligand via ether bond formation, thus providing insights into the structure-activity relationship for the improved affinity of SylA-GlbA for the CT-L activity compared to the natural compounds SylA and GlbA. Our study revealed that the novel synthetic syrbactin compound represents one of the most potent proteasome inhibitors analyzed to date and therefore exhibits promising properties for an improved drug development as an anti-cancer therapeutic.