Indolo-Phakellins as β5-Specific Noncovalent Proteasome Inhibitors
| Autor: | Jetze J. Tepe, Theresa A. Lansdell, Philipp Beck, Michael Groll, Nicole M. Hewlett |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Proteasome Endopeptidase Complex Indoles Natural product Halogen bond Dose-Response Relationship Drug Stereochemistry Drug discovery Molecular Conformation General Chemistry Piperazines Catalysis Blood cancer Structure-Activity Relationship chemistry.chemical_compound Proteasome chemistry Biochemistry Humans Peptide bond Reversible inhibition Proteasome Inhibitors |
| Zdroj: | Angewandte Chemie International Edition. 54:2830-2833 |
| ISSN: | 1433-7851 |
| DOI: | 10.1002/anie.201410168 |
| Popis: | The proteasome represents an invaluable target for the treatment of cancer and autoimmune disorders. The application of proteasome inhibitors, however, remains limited to blood cancers because their reactive headgroups and peptidic scaffolds convey unfavorable pharmacodynamic properties. Thus, the discovery of more drug-like lead structures is indispensable. In this study, we present the first structure of the proteasome in complex with an indolo-phakellin that exhibits a unique noncovalent binding mode unparalleled by all hitherto reported inhibitors. The natural product inspired pentacyclic alkaloid binds solely and specificially into the spacious S3 subpocket of the proteasomal β5 substrate binding channel, gaining major stabilization through halogen bonding with the protein backbone. The presented compound provides an ideal scaffold for the structure-based design of subunit-specific nonpeptidic proteasome-blockers. |
| Databáze: | OpenAIRE |
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