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 ϭ 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-⌿-(CH 2 -NH 2 )3-4 -His-Pro-Phe], which had a t 1/2 in blood of Ͻ5 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 Hhinge 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.

Binding to and Inhibition of Insulin-Regulated Aminopeptidase by Macrocyclic Disulfides Enhances Spine Density

“…There has been dispute in the field as to the target that mediates the memory-enhancing effects of Ang IV, because this hexapeptide has the ability to bind to other proteins (Vanderheyden, 2009;Kawas et al, 2012;Benoist et al, 2014;. Nevertheless, the hypothesis that Ang IV and its analogs improve cognitive function through IRAP inhibition by altering levels of neuropeptides in the brain and/or exerting their actions by facilitating glucose uptake in neurons have attracted the most attention (Vauquelin et al, 2002;Albiston et al, 2003;Chai et al, 2004).…”

“…There is a need for improved cognitive enhancers for the treatment of Alzheimer's disease and related disorders and it is therefore not surprising that considerable efforts have been devoted to the discovery of compounds that can mimic the positive effects of Ang IV (Wolfe, 2002;Chai et al, 2008;Gard, 2008;Wright et al, 2008Hallberg, 2009;Kawas et al, 2012;McCoy et al, 2013). Both potent and specific drug-like IRAP inhibitors (Borhade et al, 2014;Mountford et al, 2014), some with proven effects in vivo (Albiston et al, , 2011, and inhibitors with more peptidic character (Kobori et al, , 1998Wolfe, 2002;Axen et al, 2006;Axen et al, 2007;Andersson et al, 2008;Lukaszuk et al, 2008Lukaszuk et al, , 2009Hallberg, 2009) have been disclosed by us and others.…”

The Procognitive and Synaptogenic Effects of Angiotensin IV–Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System

“…Previous studies from our laboratory have demonstrated that various AngIV analogs, which act as "AT 4 receptor antagonists" possess structural homology with the dimerization domain of HGF. These analogs bind HGF with high affinity while blocking HGF dimerization and ultimately its capacity to activate c-Met (Kawas et al, 2011(Kawas et al, , 2012. Furthermore, there appears to be direct correlation between biological activity and the ability to inhibit HGF dimerization (Kawas et al, 2012).…”

“…Initial hints of a possible target are apparent in several studies that examined the mechanism of action of "AT 4 receptor antagonists" (Yamamoto et al, 2010;Kawas et al, 2011Kawas et al, , 2012, which were originally defined as AngIV-like molecules that interfered with cognition (Wright et al, 1999). These studies demonstrated that the antagonists had structural homology with the dimerization domain of the pleiotropic growth factor hepatocyte growth factor (HGF), bound to HGF with high affinity, blocked HGF's activation and subsequent activation of its receptor c-Met, and displayed both anticancer and antiangiogenic activity as would be expected of an HGF/c-Met antagonist (Peters and Adjei, 2012).…”

Local expression of AP/AngIV/IRAP and effect of AngIV on glucose-induced epithelial transport in human jejunal mucosa

“…34,37 On the other hand, AngIV has the possibility to bind and activate the hepatocyte growth factor receptor named c-Met. 38 The rate of delivery or formation, as well as elimination, are other important determinants for activity that in turn are dependent on the actual expression pattern of the RAS-associated enzymes. AngIV has been reported to be short-lived and completely degraded within five minutes.…”