Department of Veterinary and Comparative, Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, WA 99164-6520, USA.
J Pharmacol Exp Ther. 2011 Nov;339(2):509-18. doi: 10.1124/jpet.111.185694. Epub 2011 Aug 22.
The angiotensin IV analog norleual [Nle-Tyr-Leu-ψ-(CH(2)-NH(2))-Leu-His-Pro-Phe] has been shown recently to act as a hepatocyte growth factor (HGF)/Met antagonist capable of blocking the binding of HGF to the Met receptor, inhibiting HGF-dependent activation of Met, and attenuating HGF-dependent cellular activities. In addition, norleual exhibited marked anticancer activity. Homology between norleual and the dimerization domain (hinge region) of HGF led to the hypothesis that norleual acts by interfering with HGF dimerization/multimerization and functions as a dominant-negative hinge region mimic. To test this hypothesis we investigated the ability of norleual to bind to and inhibit the dimerization of HGF. To further evaluate the idea that norleual was acting as a hinge region mimic, we synthesized a hexapeptide representing the HGF hinge sequence and established its capacity to similarly block HGF-dependent activation of Met and HGF-dependent cellular functions. The hinge peptide not only bound with high affinity directly to HGF and blocked its dimerization but it also inhibited HGF-dependent Met activation, suppressed HGF-dependent cellular functions, and exhibited anticancer activity. The major implication of this study is that molecules targeting the dimerization domain of HGF may represent novel and viable anticancer therapeutic agents; the development of such molecules should be feasible using norleual and the hinge peptide as synthetic templates.
最近发现血管紧张素 IV 类似物 norleual [Nle-Tyr-Leu-ψ-(CH(2)-NH(2))-Leu-His-Pro-Phe] 可作为肝细胞生长因子 (HGF)/Met 拮抗剂，能够阻断 HGF 与 Met 受体结合，抑制 HGF 依赖的 Met 激活，并减弱 HGF 依赖的细胞活性。此外，norleual 还表现出显著的抗癌活性。norleual 与 HGF 的二聚化结构域（铰链区）之间的同源性导致了这样一种假设，即 norleual 通过干扰 HGF 的二聚化/多聚化而起作用，并作为一种显性负性铰链区模拟物发挥作用。为了验证这一假设，我们研究了 norleual 结合和抑制 HGF 二聚化的能力。为了进一步评估 norleual 作为铰链区模拟物的作用，我们合成了一个代表 HGF 铰链序列的六肽，并确定了它同样阻断 HGF 依赖的 Met 激活和 HGF 依赖的细胞功能的能力。该铰链肽不仅与 HGF 直接高亲和力结合并阻断其二聚化，而且还抑制 HGF 依赖的 Met 激活、抑制 HGF 依赖的细胞功能，并表现出抗癌活性。这项研究的主要意义是，靶向 HGF 二聚化结构域的分子可能代表新型可行的抗癌治疗剂；使用 norleual 和铰链肽作为合成模板，开发此类分子应该是可行的。
