title: Development of angiotensin IV analogs as hepatocyte growth factor/Met modifiers.
abstract: 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.
authors: Department of Veterinary and Comparative, Anatomy, Pharmacology, and Physiology, PO Box 6520, Washington State University, Pullman, WA 99164-6520, USA.
authors: Leen H
authors: LH
authors: Kawas
authors: Alene T
authors: AT
authors: McCoy
authors: Brent J
authors: BJ
authors: Yamamoto
authors: John W
authors: JW
authors: Wright
authors: Joseph W
authors: JW
authors: Harding
mesh_terms: D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004285:Dogs; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000494:pharmacology; D055503:Protein Multimerization; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D009842:Oligopeptides; C548782:norleucyl-tyrosyl-leucyl-psi(CH2-NH2)(3-4)-histidyl-prolyl-phenylalanine; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met