20S Proteasome Inhibition: Designing Noncovalent Linear Peptide Mimics of the Natural Product TMC-95A

Stop the shredder: The 20S proteasome maintains homeostasis and regulates important intracellular processes by subjecting most intracellular proteins to endoproteolytic cleavage. This complex hydrolysis machinery has received considerable attention for the treatment of many diseases, including cance...

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Veröffentlicht in:	ChemMedChem 2010-10, Vol.5 (10), p.1701-1705
Hauptverfasser:	Groll, Michael, Gallastegui, Nerea, Maréchal, Xavier, Le Ravalec, Virginie, Basse, Nicolas, Richy, Nicolas, Genin, Emilie, Huber, Robert, Moroder, Luis, Vidal, Joëlle, Reboud-Ravaux, Michèle
Format:	Artikel
Sprache:	eng
Schlagworte:	Binding Sites Catalytic Domain Chemical Sciences crystallographic analysis Crystallography, X-Ray enzymes inhibitors natural products Organic chemistry Peptides, Cyclic - chemistry Peptides, Cyclic - pharmacology Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Proteasome Endopeptidase Complex - metabolism Proteasome Inhibitors proteasomes
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Zusammenfassung:	Stop the shredder: The 20S proteasome maintains homeostasis and regulates important intracellular processes by subjecting most intracellular proteins to endoproteolytic cleavage. This complex hydrolysis machinery has received considerable attention for the treatment of many diseases, including cancer. We report a new set of noncovalent peptide mimics based on TMC‐95A and our rational approach to inhibitor optimization using both crystallographic and kinetic studies.
ISSN:	1860-7179 1860-7187
DOI:	10.1002/cmdc.201000293