Journal article
Development of angiotensin IV analogs as hepatocyte growth factor/Met modifiers
The Journal of pharmacology and experimental therapeutics, Vol.340(3), pp.539-548
03/2012
Handle:
https://hdl.handle.net/2376/109243
PMID: 22129598
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.
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Details
- Title
- Development of angiotensin IV analogs as hepatocyte growth factor/Met modifiers
- Creators
- Leen H Kawas - Department of Veterinary and Comparative, Anatomy, Pharmacology, and Physiology, PO Box 6520, Washington State University, Pullman, WA 99164-6520, USAAlene T McCoyBrent J YamamotoJohn W WrightJoseph W Harding
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.340(3), pp.539-548
- Academic Unit
- Psychology, Department of; Integrative Physiology and Neuroscience, Department of
- Publisher
- United States
- Identifiers
- 99900547699301842
- Language
- English
- Resource Type
- Journal article