title: α- and β-hydrazino acid-based pseudopeptides inhibit the chymotrypsin-like activity of the eukaryotic 20S proteasome.
abstract: We describe the synthesis of a library of new pseudopeptides and their inhibitory activity of the rabbit 20S proteasome chymotrypsin-like (ChT-L) activity. We replaced a natural α-amino acid by an α- or a β-hydrazino acid and obtained inhibitors of proteasome up to a submicromolar range (0.7 μM for molecule 24b). Structural variations influenced the inhibition of the ChT-L activity. Models of inhibitor/20S proteasome complexes corroborated the inhibition efficacies obtained by kinetic studies.
authors.affiliation: Molécules Fluorées et Chimie Médicinale, BioCIS UMR-CNRS 8076, LabEx LERMIT, Université Paris-Sud 11, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bordessa
authors.forename: Massaba
authors.initials: M
authors.lastname: Keita
authors.forename: Xavier
authors.initials: X
authors.lastname: Maréchal
authors.forename: Lucia
authors.initials: L
authors.lastname: Formicola
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lagarde
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodrigo
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bernadat
authors.forename: Cyril
authors.initials: C
authors.lastname: Bauvais
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Soulier
authors.forename: Laure
authors.initials: L
authors.lastname: Dufau
authors.forename: Thierry
authors.initials: T
authors.lastname: Milcent
authors.forename: Benoit
authors.initials: B
authors.lastname: Crousse
authors.forename: Michèle
authors.initials: M
authors.lastname: Reboud-Ravaux
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ongeri
mesh_terms: D000818:Animals; D002918:Chymotrypsin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D006834:Hydrazines; D010455:Peptides; D061988:Proteasome Inhibitors; D002918:Chymotrypsin
keywords: Chymotrypsin; Fluorine; Hydrazino acid; Proteasome inhibitors; Pseudopeptide; Trifluoromethyl