Noncovalent inhibition of 20S proteasome by pegylated dimerized inhibitors

作者：Marechal Xavier; Pujol Anais; Richy Nicolas; Genin Emilie; Basse Nicolas; Reboud Ravaux Michele; Vidal Joelle^*

来源：European Journal of Medicinal Chemistry, 2012, 52: 322-327.

DOI：10.1016/j.ejmech.2012.02.052

• Proteasome inhibitors
• Bivalent inhibitors
• Pegylation
• PEG conjugates
• Multivalency
• TMC-95A linear analogues

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.

• 出版日期2012-6