An ultrahigh affinity d-peptide antagonist of MDM2

Changyou Zhan, Le Zhao, Xiaoli Wei, Xueji Wu, Xishan Chen, Weirong Yuan, Wei Yue Lu, Marzena Pazgier*, Wuyuan Lu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


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-α, β, γ. The prototypic d-peptide inhibitor DPMI-α binds (25-109)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-δ, of which the binding affinity for (25-109)MDM2 has been improved over DPMI-α by 3 orders of magnitude (K d = 220 pM). X-ray crystallographic studies validate DPMI-δ as an exceedingly potent inhibitor of the p53-MDM2 interaction, promising to be a highly attractive lead drug candidate for anticancer therapeutic development.

Original languageEnglish
Pages (from-to)6237-6241
Number of pages5
JournalJournal of Medicinal Chemistry
Issue number13
StatePublished - 12 Jul 2012
Externally publishedYes


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