Baldisserotto Anna, Marastoni Mauro, Fiorini Stella, Pretto Loretta, Ferretti Valeria, Gavioli Riccardo, Tomatis Roberto
Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, Via Fossato di Mortara 17-19, I-44100 Ferrara, Italy.
Bioorg Med Chem Lett. 2008 Mar 15;18(6):1849-54. doi: 10.1016/j.bmcl.2008.02.016. Epub 2008 Feb 10.
The 20S proteasome is a multicatalytic protease complex responsible for the degradation of many proteins in mammalian cells. Specific inhibition of proteasome enzymatic subunits represents a topic of great interest for the development of new drug therapies. Following our previous development of a new class of peptide-based inhibitors bearing a C-terminal vinyl ester residue as a pharmacophoric unit that are able to interact with the catalytic threonine, we report here the synthesis and biological properties of a new series of vinyl ester cyclopeptide analogues. Some of these derivatives were shown to inhibit the chymotrypsin-like activity of the proteasome at nanomolar concentration and their potency was found to depend on the size of the tetrapeptidic cyclic portion.
20S蛋白酶体是一种多催化蛋白酶复合体，负责哺乳动物细胞中多种蛋白质的降解。蛋白酶体酶亚基的特异性抑制是新药疗法开发中备受关注的一个课题。在我们之前开发了一类以C端乙烯基酯残基作为药效基团单元、能够与催化苏氨酸相互作用的新型肽基抑制剂之后，我们在此报告一系列新型乙烯基酯环肽类似物的合成及生物学特性。其中一些衍生物在纳摩尔浓度下就能抑制蛋白酶体的类胰凝乳蛋白酶活性，并且发现它们的效力取决于四肽环部分的大小。
