An Ultrahigh Affinity d-Peptide Antagonist Of MDM2

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• 作者：Changyou Zhan ; Le Zhao ; Xiaoli Wei ; Xueji Wu ; Xishan Chen ; Weirong Yuan ; Wei-Yue Lu ; Marzena Pazgier ; Wuyuan Lu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：July 12, 2012
• 年：2012
• 卷：55
• 期：13
• 页码：6237-6241
• 全文大小：286K
• 年卷期：v.55,no.13(July 12, 2012)
• ISSN：1520-4804

文摘

The oncoprotein MDM2 negatively regulates the activity and stability of the p53 tumor suppressor and is an important molecular target for anticancer therapy. Aided by mirror image phage display and native chemical ligation, we have previously discovered several proteolysis-resistant duodecimal d-peptide antagonists of MDM2, termed ^DPMI-伪, 尾, 纬. The prototypic d-peptide inhibitor ^DPMI-伪 binds ^(25鈥?09)MDM2 at an affinity of 220 nM and kills tumor cells in vitro and inhibits tumor growth in vivo by reactivating the p53 pathway. Herein, we report the design of a superactive d-peptide antagonist of MDM2, termed ^DPMI-未, of which the binding affinity for ^(25鈥?09)MDM2 has been improved over ^DPMI-伪 by 3 orders of magnitude (K_d = 220 pM). X-ray crystallographic studies validate ^DPMI-未 as an exceedingly potent inhibitor of the p53鈥揗DM2 interaction, promising to be a highly attractive lead drug candidate for anticancer therapeutic development.