title: Noncovalent inhibition of 20S proteasome by pegylated dimerized inhibitors.
abstract: We exploited the concept of polyvalent interactions to produce highly selective and efficient inhibitors of eukaryotic proteasome. This multicatalytic protease with the unique topography of its 6 active sites has emerged as a promising target to treat cancer with the use of the covalent inhibitor bortezomib. We used our reference noncovalent inhibitor, a selective TMC-95A tripeptide linear mimic, to design dimeric noncovalent proteasome inhibitors that target two active sites simultaneously. We synthesized pegylated monomer and dimers of the reference inhibitor and evaluated their capacity to inhibit a mammalian 20S proteasome. The inhibitory power of the dimers depended on the average length of their spacer. Lineweaver-Burk double-reciprocal plots indicated competitive inhibition. The best dimer inhibited CT-L activity 800-times more efficiently than the reference inhibitor.
authors.affiliation: Enzymologie Moléculaire et Fonctionnelle, UR4, University Paris 6-Pierre et Marie Curie, UPMC-Sorbonne Universités, case 256, 7 quai Saint Bernard, 75252 Paris Cedex 05, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Maréchal
authors.forename: Anaïs
authors.initials: A
authors.lastname: Pujol
authors.forename: Nicolas
authors.initials: N
authors.lastname: Richy
authors.forename: Emilie
authors.initials: E
authors.lastname: Genin
authors.forename: Nicolas
authors.initials: N
authors.lastname: Basse
authors.forename: Michèle
authors.initials: M
authors.lastname: Reboud-Ravaux
authors.forename: Joëlle
authors.initials: J
authors.lastname: Vidal
mesh_terms: D000818:Animals; D019281:Dimerization; D010456:Peptides, Cyclic / Q000737:chemistry; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D011817:Rabbits
chemical_list: D010456:Peptides, Cyclic; D057786:Peptidomimetics; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; C408291:TMC-95A; D011092:Polyethylene Glycols