Noncovalent inhibition of 20S proteasome by pegylated dimerized inhibitors.
Eur J Med Chem
; 52: 322-7, 2012 Jun.
Article
de En
| MEDLINE
| ID: mdl-22440858
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Polyéthylène glycols
/
Inhibiteurs de protéases
/
Dimérisation
/
Peptidomimétiques
/
Inhibiteurs du protéasome
Limites:
Animals
Langue:
En
Journal:
Eur J Med Chem
Année:
2012
Type de document:
Article
Pays d'affiliation:
France