Basse Nicolas, Piguel Sandrine, Papapostolou David, Ferrier-Berthelot Alexandra, Richy Nicolas, Pagano Maurice, Sarthou Pierre, Sobczak-Thépot Joëlle, Reboud-Ravaux Michèle, Vidal Joëlle
Laboratoire d'Enzymologie Moléculaire et Fonctionnelle, FRE 2852, CNRS, Université de Paris VI, Institut Jacques Monod, T43, 2 Place Jussieu, F 75251 Paris Cedex 05, France.
J Med Chem. 2007 Jun 14;50(12):2842-50. doi: 10.1021/jm0701324. Epub 2007 May 19.
We have designed and evaluated 45 linear analogues of the natural constrained cyclopeptide TMC-95A. These synthetically less demanding molecules are based on the tripeptide sequence Y-N-W of TMC-95A. Structural variations in the amino acid side chains and termini greatly influenced both the efficiency and selectivity of action on a given type of active site. Inhibition constants were submicromolar (Ki approximately 300 nM) despite the absence of the entropically favorable constrained conformation that is characteristic of TMC-95A and its cyclic analogues. These linear compounds were readily prepared and reasonably stable in culture medium and could be optimized to inhibit one, two, or all three proteasome catalytic sites. Cytotoxicity assays performed on a series of human tumor cell lines identified the most potent inhibitors in cells.
我们设计并评估了天然受限环肽TMC - 95A的45种线性类似物。这些合成要求较低的分子基于TMC - 95A的三肽序列Y - N - W。氨基酸侧链和末端的结构变化极大地影响了对给定类型活性位点的作用效率和选择性。尽管缺乏TMC - 95A及其环状类似物所特有的熵有利受限构象，但抑制常数仍为亚微摩尔级（Ki约为300 nM）。这些线性化合物易于制备且在培养基中相当稳定，并且可以进行优化以抑制一个、两个或所有三个蛋白酶体催化位点。对一系列人类肿瘤细胞系进行的细胞毒性测定确定了细胞中最有效的抑制剂。
