Design and synthesis of Selenazole-containing peptides for cocrystallization with P-glycoprotein.
Design and synthesis of Selenazole-containing peptides for cocrystallization with P-glycoprotein.
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DOI：
10.1002/cbic.201100048
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发表时间：
2011-04-11
期刊：
影响因子：
--
通讯作者：
Zhang Q
中科院分区：
文献类型：
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作者：
Tao H;Weng Y;Zhuo R;Chang G;Urbatsch IL;Zhang Q
P-糖蛋白（P-glycoprotein，Pgp）在某些肿瘤细胞中的过度表达是导致化疗失败的多药耐药（multidrug resistance，MDR）的主要原因。因此，Pgp一直是药物开发的长期目标，希望在临床肿瘤学中规避MDR。[1，2]超过三十年的生物化学研究表明，Pgp可能在位于两个跨膜结构域之间的大的柔性区域内具有几个不同的底物结合位点;这些位点识别数百种化学上不相关的化合物，包括大多数传统抗癌药物。[3-6]这些化合物可以通过Pgp使用由自催化ATP水解释放的能量结合实质性构象变化从细胞中输出。我们的小组最近确定了小鼠Pgp的结构在3.8 μ m分辨率的X射线衍射。[7]我们还解析了Pgp与一对对映体环肽QZ 59 Se-RRR和QZ 59 Se-SSS的共晶结构（方案1），其中两种对映体以不同的化学计量和在向细胞质侧开放的跨膜门户内的不同位点与Pgp结合。这些结构提供了第一次瞥见的多特异性药物结合位点的Pgp在原子detail.Scheme 1概述了我们的策略硒（Se）标记的环肽的设计和合成，是至关重要的成功共结晶与Pgp的X-射线结构测定。我们早期尝试将Pgp与几种充分研究的调节剂共结晶，包括环孢菌素A [8，9]和环孢菌素衍生物PSC 833 [10]，但没有成功。环孢菌素A和PSC 833都是大环十一聚体肽，其溶液相构象是柔性的。[11我们假设这种构象柔性
Over-expression of P-glycoprotein (Pgp) in some cancer cells is a primary cause of multidrug resistance (MDR) that results in chemotherapy failure. As a consequence, Pgp has been a long-sought target for drug development in the hope of circumventing MDR in clinical oncology.[1, 2] More than three decades of biochemical studies have indicated that Pgp might possess several distinct substrate-binding sites within a large, flexible region located between the two transmembrane domains; these sites recognize hundreds of chemically unrelated compounds, including a majority of traditional anti-cancer drugs.[3–6] These compounds can be exported from cells by Pgp using energy released by self-catalyzed ATP hydrolysis in conjunction with substantial conformational changes. Our groups recently determined a structure of mouse Pgp at 3.8 Å resolution by X-ray diffraction.[7] We also solved the cocrystal structures of Pgp with a pair of enantiomeric cyclic peptides, QZ59Se-RRR and QZ59Se-SSS (Scheme 1), in which the two enantiomers bind to Pgp with different stoichiometries and at distinct sites within a transmembrane portal open to the cytoplasmic side. These structures provided the first glimpse of the polyspecific drug-binding site of Pgp in atomic detail.Scheme 1 outlines our strategies for the design and synthesis of selenium (Se)-labeled cyclic peptides that were crucial to the successful cocrystallization with Pgp for X-ray structure determination. Our early attempts to cocrystallize Pgp with several well-studied modulators, including cyclosporin A [8, 9] and the cyclosporin derivative PSC 833 [10] were unsuccessful. Cyclosporin A and PSC 833 are both macrocyclic undecamer peptides the solution-phase conformations of which are flexible.[11, 12] We assume that this conformational flexibility