Incorporation of non-natural amino acids improves cell permeability and potency of specific inhibitors of proteasome trypsin-like sites.
Incorporation of non-natural amino acids improves cell permeability and potency of specific inhibitors of proteasome trypsin-like sites.
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DOI：
10.1021/jm3016987
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发表时间：
2013-02-14
影响因子：
7.3
通讯作者：
Kisselev, Alexei F.
中科院分区：
文献类型：
--
作者：
Geurink, Paul P.;van der Linden, Wouter A.;Mirabella, Anne C.;Gallastegui, Nerea;de Bruin, Gerjan;Blom, Annet E. M.;Voges, Mathias J.;Mock, Elliot D.;Florea, Bogdan I.;van der Marel, Gijs A.;Driessen, Christoph;van der Stelt, Mario;Groll, Michael;Overkleeft, Herman S.;Kisselev, Alexei F.
蛋白酶体通过三对不同的活性位点的协同作用降解哺乳动物细胞中的大多数蛋白质。凝乳胰蛋白酶样位点是抗骨髓瘤药物硼替佐米和卡非佐米的靶点。胰蛋白酶样位点的抑制剂使多发性骨髓瘤细胞对这些药物敏感。在这里，我们描述了系统的努力，以开发具有改善效力和细胞渗透性的抑制剂，产生叠氮- ph - leu - leu -4-氨基甲基- ph -甲基乙烯基砜（4a, LU-102），以及基于荧光活性的该位点探针。4a及相关抑制剂与酵母蛋白酶体络合的x射线结构揭示了特异性的结构基础。当作为单一药物使用时对骨髓瘤细胞无毒，4a使它们对硼替佐米和卡非佐米敏感。这种致敏作用比组蛋白乙酰化酶抑制剂的协同作用或阿霉素和地塞米松的附加作用强得多，这提高了胰蛋白酶样位点抑制剂与硼替佐米或卡非佐米联合使用比目前临床使用的联合使用具有更强的抗肿瘤活性的可能性。
Proteasomes degrade the majority of proteins in mammalian cells by a concerted action of three distinct pairs of active sites. The chymotrypsin-like sites are targets of antimyeloma agents bortezomib and carfilzomib. Inhibitors of the trypsin-like site sensitize multiple myeloma cells to these agents. Here we describe systematic effort to develop inhibitors with improved potency and cell permeability, yielding azido-Phe-Leu-Leu-4-aminomethyl-Phe-methyl vinyl sulfone (4a, LU-102), and a fluorescent activity-based probe for this site. X-ray structures of 4a and related inhibitors complexed with yeast proteasomes revealed the structural basis for specificity. Nontoxic to myeloma cells when used as a single agent, 4a sensitized them to bortezomib and carfilzomib. This sensitizing effect was much stronger than the synergistic effects of histone acetylase inhibitors or additive effects of doxorubicin and dexamethasone, raising the possibility that combinations of inhibitors of the trypsin-like site with bortezomib or carfilzomib would have stronger antineoplastic activity than combinations currently used clinically.
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影响因子：
16
作者：
Köhler, A;Cascio, P;Finley, D
通讯作者：
Finley, D
影响因子：
56.9
作者：
LOWE, J;STOCK, D;HUBER, R
通讯作者：
HUBER, R
影响因子：
4.8
作者：
Kisselev, AF;Callard, A;Goldberg, AL
通讯作者：
Goldberg, AL
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
影响因子：
64.8
作者：
Groll, M;Ditzel, L;Huber, R
通讯作者：
Huber, R