Structure-based design of human immuno- and constitutive proteasomes inhibitors
2018
Starting from the X-ray structure of our previous
tripeptidiclinear mimics of TMC-95A in complex with yeast 20S
proteasome, we introduced new structural features to induce a differential inhibition between human constitutive and immunoproteasome 20S particles. Libraries of 24
tripeptidicand 6
dipeptidicderivatives were synthesized. The optimized preparation of 3-hydroxyoxindolyl alanine residues from tryptophan and their incorporation in peptides were described. Several potent inhibitors of human constitutive
proteasomeand immunoproteasome acting at the nanomolar level (IC50 = 7.1 nM against the
chymotrypsin-like activity for the best inhibitor) were obtained. A cytotoxic effect at the submicromolar level was observed against 6 human cancer cell lines. © 2018 Elsevier Masson SAS
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