Clerc, Jérôme; Groll, Michael; Illich, Damir J.; Bachmann, André S.; Huber, Robert; Schellenberg, Barbara; Dudler, Robert; Kaiser, Markus:
Synthetic and structural studies on Syringolin A and B reveal critical determinants for selectivity and potency of proteasome inhibition
In: Proceedings of the National Academy of Sciences of the United States of America (PNAS), Jg. 106 (2009), Heft 16, S. 6507 - 6512
2009Artikel/Aufsatz in Zeitschrift
BiologieFakultät für BiologieForschungszentren » Zentrum für Medizinische Biotechnologie (ZMB)
Damit verbunden: 1 Publikation(en)
Titel:
Synthetic and structural studies on Syringolin A and B reveal critical determinants for selectivity and potency of proteasome inhibition
Autor*in:
Clerc, Jérôme;Groll, Michael;Illich, Damir J.;Bachmann, André S.;Huber, RobertUDE
LSF ID
13552
ORCID
0000-0002-0133-5334ORCID iD
Sonstiges
der Hochschule zugeordnete*r Autor*in
;
Schellenberg, Barbara;Dudler, Robert;Kaiser, MarkusUDE
LSF ID
52590
ORCID
0000-0002-6540-8520ORCID iD
Sonstiges
der Hochschule zugeordnete*r Autor*in
Erscheinungsjahr:
2009

Abstract:

Syrbactins, a family of natural products belonging either to the syringolin or glidobactin class, are highly potent proteasome inhibitors. Although sharing similar structural features, they differ in their macrocyclic lactam core structure and exocyclic side chain. These structural variations critically influence inhibitory potency and proteasome subsite selectivity. Here, we describe the total synthesis of syringolin A and B, which together with enzyme kinetic and structural studies, allowed us to elucidate the structural determinants underlying the proteasomal subsite selectivity and binding affinity of syrbactins. These findings were used successfully in the rational design and synthesis of a syringolin A-based lipophilic derivative, which proved to be the most potent syrbactin-based proteasome inhibitor described so far. With a Ki′ of 8.65 ± 1.13 nM for the chymotryptic activity, this syringolin A derivative displays a 100-fold higher potency than the parent compound syringolin A. In light of the medicinal relevance of proteasome inhibitors as anticancer compounds, the present findings may assist in the rational design and development of syrbactin-based chemotherapeutics.