The 6-AH family [D-Nle-X-Ile-NH-(CH2)5-CONH2; where X= various amino acids] of Angiotensin IV analogs, bind 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-(CH2)5-CONH2, had a t1/2 in blood of 80 minutes compared to the parent compound Norleual (Nle-Tyr-Leu-Ψ-(CH2-NH2)3-4-His-Pro-Phe), which had a t1/2 in blood of < 5 Minutes. 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 3H-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 reaching 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. Further, 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 AngIV analogs exert their biological activity by modifying the activity of the HGF/Met system and offer the potential as therapeutic agents in disorders that are dependent on or possess an over-activation of the HGF/Met system.
- Received September 16, 2011.
- Revision received November 28, 2011.
- Accepted November 29, 2011.
- The American Society for Pharmacology and Experimental Therapeutics