The Angiotensin IV Analog Nle-Tyr-Leu-ψ-(CH2-NH2)3-4-His-Pro-Phe (Norleual) Can Act as a Hepatocyte Growth Factor/c-Met Inhibitor

Yamamoto, Brent; Elias, Patrick D.; Masino, John A.; Hudson, Bryan D.; McCoy, Alene T.; Anderson, Zach J.; Varnum, Michael D.; Sardinia, Michael F.; Wright, John W.; Harding, Joseph W.

doi:10.1124/jpet.109.161711

Cited by 39 publications

(47 citation statements)

References 38 publications

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“…The Ang IV-related peptidomimetic norleual was previously shown to possess anti-HGF/Met, antiangiogenic, and anticancer activities (Yamamoto et al, 2010). The presence of unprotected peptide bonds at both the amino-and carboxyl-terminal linkages predicts that norleual should have poor metabolic stability and rapid clearance for the circulation, properties that may limit its clinical utility.…”

Section: Resultsmentioning

confidence: 99%

“…This dimer is arranged in a head to tail orientation; the dimer interface comprises a central region, the hinge region that is important for the proper dimer formation and orientation. A homologous sequence-conservation screen against all possible transcripts that were independent of and not derived from angiotensinogen looking for similarities to Ang IV identified partial homology with the hinge region (Yamamoto et al, 2010) of the plasminogen family of proteins, which include plasminogen itself, its antiangiogenic degradation …”

Section: Resultsmentioning

confidence: 99%

“…Thus, we have targeted the dimerization process by developing molecules that mimic the dimerization domain, the hinge region, with idea that they can act as dominant negative replacements. Recent studies have validated this general approach, demonstrating that molecules designed around angiotensin IV (Yamamoto et al, 2010) or the hinge sequence itself (Kawas et al, 2011) can bind HGF, block its dimerization, and attenuate HGF-dependent cellular actions. The studies described herein represent a first step toward producing useful therapeutics targeted at HGF dimerization.…”

Section: Discussionmentioning

confidence: 99%

“…The studies described herein represent a first step toward producing useful therapeutics targeted at HGF dimerization. The primary focus of this study was to improve the pharmacokinetic characteristics of a parent compound norleual (Yamamoto et al, 2010) while maintaining biological activity. To this end, we successfully synthesized and evaluated a family of new molecules, the 6-AH family [D-Nle-X-Ile-NH-(CH 2 ) 5 -COOH].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies from our laboratory (Yamamoto et al, 2010) have shown that picomolar concentrations of the Ang IV analog norleual [(Nle-Tyr-Leu--(CH 2 -NH 2 ) [3][4] -His-Pro-Phe)] are capable of potently inhibiting the HGF/Met system and binding directly to the hinge region of HGF blocking its dimerization (Kawas et al, 2011). Moreover, a hexapeptide representing the actual hinge region possessed biochemical and pharmacological properties identical to norleuals (Kawas et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Development of Angiotensin IV Analogs as Hepatocyte Growth Factor/Met Modifiers

Kawas¹,

McCoy²,

Yamamoto³

et al. 2011

J Pharmacol Exp Ther

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Development of Angiotensin IV Analogs as Hepatocyte Growth Factor/Met Modifiers

Kawas¹,

McCoy²,

Yamamoto³

et al. 2011

J Pharmacol Exp Ther

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Neuropeptides: Metabolism to Bioactive Fragments and the Pharmacology of Their Receptors

Hallberg

2014

Medicinal Research Reviews

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The proteolytic processing of neuropeptides has an important regulatory function and the peptide fragments resulting from the enzymatic degradation often exert essential physiological roles. The proteolytic processing generates, not only biologically inactive fragments, but also bioactive fragments that modulate or even counteract the response of their parent peptides. Frequently, these peptide fragments interact with receptors that are not recognized by the parent peptides. This review discusses tachykinins, opioid peptides, angiotensins, bradykinins, and neuropeptide Y that are present in the central nervous system and their processing to bioactive degradation products. These well-known neuropeptide systems have been selected since they provide illustrative examples that proteolytic degradation of parent peptides can lead to bioactive metabolites with different biological activities as compared to their parent peptides. For example, substance P, dynorphin A, angiotensin I and II, bradykinin, and neuropeptide Y are all degraded to bioactive fragments with pharmacological profiles that differ considerably from those of the parent peptides. The review discusses a selection of the large number of drug-like molecules that act as agonists or antagonists at receptors of neuropeptides. It focuses in particular on the efforts to identify selective drug-like agonists and antagonists mimicking the effects of the endogenous peptide fragments formed. As exemplified in this review, many common neuropeptides are degraded to a variety of smaller fragments but many of the fragments generated have not yet been examined in detail with regard to their potential biological activities. Since these bioactive fragments contain a small number of amino acid residues, they provide an ideal starting point for the development of drug-like substances with ability to mimic the effects of the degradation products. Thus, these substances could provide a rich source of new pharmaceuticals. However, as discussed herein relatively few examples have so far been disclosed of successful attempts to create bioavailable, drug-like agonists or antagonists, starting from the structure of endogenous peptide fragments and applying procedures relying on stepwise manipulations and simplifications of the peptide structures.

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The brain renin–angiotensin system: a diversity of functions and implications for CNS diseases

Wright

Harding

2012

Pflugers Arch - Eur J Physiol

190

145

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The classic renin-angiotensin system (RAS) was initially described as a hormone system designed to mediate cardiovascular and body water regulation, with angiotensin II as its major effector. The discovery of an independent local brain RAS composed of the necessary functional components (angiotensinogen, peptidases, angiotensins, and specific receptor proteins) significantly expanded the possible physiological and pharmacological functions of this system. This review first describes the enzymatic pathways resulting in active angiotensin ligands and their interaction with AT(1), AT(2), and AT(4) receptor subtypes. Next, we discuss the classic physiologies and behaviors controlled by the RAS including cardiovascular, thirst, and sodium appetite. A final section summarizes non-classic functions and clinical conditions mediated by the brain RAS with focus on memory and Alzheimer's disease. There is no doubt that the brain RAS is an important component in the development of dementia. It also appears to play a role in normal memory consolidation and retrieval. The presently available anti-dementia drugs are proving to be reasonably ineffective, thus alternative treatment approaches must be developed. At the same time, presently available drugs must be tested for their efficacy to treat newly identified syndromes and diseases connected with the RAS. The list of non-classic physiologies and behaviors is ever increasing in both number and scope, attesting to the multidimensional influences of the RAS. Such diversity in function presents a dilemma for both researchers and clinicians. Namely, the blunting of RAS subsystems in the hopes of combating one constellation of underlying causes and disease symptoms may be counter-balanced by unanticipated and unwanted consequences to another RAS subsystem. For example, the use of angiotensin-converting enzyme inhibitors and AT(1) and/or AT(2) receptor blockers have shown great promise in the treatment of cardiovascular related pathologies; however, their use could negate the cerebroprotective benefits offered by this system.

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The Angiotensin IV Analog Nle-Tyr-Leu-ψ-(CH₂-NH₂)^3-4-His-Pro-Phe (Norleual) Can Act as a Hepatocyte Growth Factor/c-Met Inhibitor

Cited by 39 publications

References 38 publications

Development of Angiotensin IV Analogs as Hepatocyte Growth Factor/Met Modifiers

Development of Angiotensin IV Analogs as Hepatocyte Growth Factor/Met Modifiers

Neuropeptides: Metabolism to Bioactive Fragments and the Pharmacology of Their Receptors

The brain renin–angiotensin system: a diversity of functions and implications for CNS diseases

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