Department of Veterinary and Comparative, Anatomy, Pharmacology, and Physiology, PO Box 6520, Washington State University, Pullman, WA 99164-6520, USA.
J Pharmacol Exp Ther. 2012 Mar;340(3):539-48. doi: 10.1124/jpet.111.188136. Epub 2011 Nov 30.
The 6-AH family [D-Nle-X-Ile-NH-(CH(2))(5)-CONH(2); where X = various amino acids] of angiotensin IV (Ang IV) analogs binds directly to hepatocyte growth factor (HGF) and inhibit HGF's ability to form functional dimers. The metabolically stabilized 6-AH family member, D-Nle-Tyr-Ile-NH-(CH(2))(5)-CONH(2,) had a t(1/2) in blood of 80 min compared with the parent compound norleual [Nle-Tyr-Leu-Ψ-(CH(2)-NH(2))(3-4)-His-Pro-Phe], which had a t(1/2) in blood of <5 min. 6-AH family members were found to act as mimics of the dimerization domain of HGF (hinge region) and inhibited the interaction of an HGF molecule with a (3)H-hinge region peptide resulting in an attenuated capacity of HGF to activate its receptor Met. This interference translated into inhibition of HGF-dependent signaling, proliferation, and scattering in multiple cell types at concentrations down into the low picomolar range. We also noted a significant correlation between the ability of the 6-AH family members to block HGF dimerization and inhibition of the cellular activity. Furthermore, a member of the 6-AH family with cysteine at position 2, was a particularly effective antagonist of HGF-dependent cellular activities. This compound suppressed pulmonary colonization by B16-F10 murine melanoma cells, which are characterized by an overactive HGF/Met system. Together, these data indicate that the 6-AH family of Ang IV analogs exerts its biological activity by modifying the activity of the HGF/Met system and offers the potential as therapeutic agents in disorders that are dependent on or possess an overactivation of the HGF/Met system.
血管紧张素 IV（Ang IV）类似物的 6-AH 家族[D-Nle-X-Ile-NH-（CH(2))(5)-CONH(2)；其中 X 为各种氨基酸]直接与肝细胞生长因子（HGF）结合，并抑制 HGF 形成功能性二聚体的能力。代谢稳定的 6-AH 家族成员 D-Nle-Tyr-Ile-NH-（CH(2))(5)-CONH(2,)在血液中的半衰期为 80 分钟，而母体化合物 norleual[Nle-Tyr-Leu-Ψ-（CH(2)-NH(2))(3-4)-His-Pro-Phe]在血液中的半衰期<5 分钟。研究发现，6-AH 家族成员可作为 HGF（铰链区）二聚化结构域的模拟物，抑制 HGF 分子与[3H-hinge region]肽的相互作用，从而减弱 HGF 激活其受体 Met 的能力。这种干扰转化为抑制 HGF 依赖性信号转导、增殖和多种细胞类型的散射，其浓度低至皮摩尔范围。我们还注意到，6-AH 家族成员阻断 HGF 二聚化的能力与抑制细胞活性之间存在显著相关性。此外，6-AH 家族中第 2 位为半胱氨酸的成员，是 HGF 依赖性细胞活性的特别有效拮抗剂。该化合物抑制了 B16-F10 小鼠黑色素瘤细胞的肺定植，B16-F10 小鼠黑色素瘤细胞的 HGF/Met 系统过度活跃。这些数据表明，血管紧张素 IV 类似物的 6-AH 家族通过改变 HGF/Met 系统的活性发挥其生物学活性，并为依赖或过度激活 HGF/Met 系统的疾病提供了作为治疗剂的潜力。
