Institute of Human Virology & Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
J Med Chem. 2012 Jul 12;55(13):6237-41. doi: 10.1021/jm3005465. Epub 2012 Jun 22.
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 (D)PMI-α, β, γ. The prototypic d-peptide inhibitor (D)PMI-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 (D)PMI-δ, of which the binding affinity for ((25-109))MDM2 has been improved over (D)PMI-α by 3 orders of magnitude (K(d) = 220 pM). X-ray crystallographic studies validate (D)PMI-δ as an exceedingly potent inhibitor of the p53-MDM2 interaction, promising to be a highly attractive lead drug candidate for anticancer therapeutic development.
癌蛋白 MDM2 负调控 p53 肿瘤抑制因子的活性和稳定性，是抗癌治疗的重要分子靶点。在镜像噬菌体展示和天然化学连接的辅助下，我们之前发现了几种对 MDM2 具有抗降解作用的十二元 d-肽拮抗剂，称为 (D)PMI-α、β、γ。原型 d-肽抑制剂 (D)PMI-α 以 220 nM 的亲和力与 ((25-109))MDM2 结合，并通过重新激活 p53 通路在体外杀死肿瘤细胞和在体内抑制肿瘤生长。在此，我们报告了一种对 MDM2 具有超强活性的 d-肽拮抗剂 (D)PMI-δ 的设计，其对 ((25-109))MDM2 的结合亲和力相对于 (D)PMI-α 提高了 3 个数量级 (K(d) = 220 pM)。X 射线晶体学研究证实 (D)PMI-δ 是一种极其有效的 p53-MDM2 相互作用抑制剂，有望成为一种极具吸引力的抗癌治疗开发的先导药物候选物。
