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Hepatocyte growth factor mimetics as therapeutic agents

A hepatocyte growth factor and simulant technology, which is applied in the field of hepatocyte growth factor simulants as therapeutic agents, can solve the problems of preventing blood-brain barrier permeability, restricting widespread use, and high cost

Active Publication Date: 2015-09-30
WASHINGTON STATE UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0029] Limitations of direct use of HGF: Direct use of HGF or any other protein neurotrophic factor as a therapeutic agent has two serious limitations: 1) the large size and hydrophilic nature prevent its blood-brain barrier (BBB) ​​penetration; and 2) The cost of production by recombinant methods is so high that it limits their widespread use

Method used

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  • Hepatocyte growth factor mimetics as therapeutic agents
  • Hepatocyte growth factor mimetics as therapeutic agents
  • Hepatocyte growth factor mimetics as therapeutic agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0172] Embodiment 1Dihexa and Nle 1 - AnglV regulates synaptogenesis.

[0173] Nle of AngIV has been found before 1 - Tetrapeptide of AngIV analog (Nle 1 -YIH) and tripeptide (Nle 1 -YI) fragments are the minimally active fragments capable of overcoming scopolamine-induced cognitive impairment in a spatial learning task. Using the tripeptide as a novel template, additional active analogs with improved metabolic capacity, blood-brain barrier permeability, and oral efficacy were synthesized. In this example, we demonstrate the novel, orally active, angiotensin IV analog, Dihexa. Materials and Methods

[0174] Animals and Surgery. Male Sprague-Dawley rats (Taconic origin) weighing 390-450 g had free access to food and water (Harland Tekland F6 Rat Chow, Madison, WI) except when food was removed the night before surgery. Each animal was anesthetized with ketamine hydrochloride and xylazine (100 and 2 mg / kg intramuscularly, respectively; Phoenix Scientific; St. Joseph, MO, a...

Embodiment 2

[0204] Example 2. Target of AngIV analogs is liver growth factor

[0205] This example shows that the novel angiotensin IV ligand Dihexa and its parent molecule Nle 1 - AngIV acts through the HGF / c-Met receptor system.

[0206] Materials and Methods

[0207] Animals and Surgery

[0208] Male Sprague-Dawley rats (Taconic origin) weighing 390-450 g had free access to food and water (Harland Tekland F6 Rat Chow, Madison, WI) except when food was removed the night before surgery. Each animal was anesthetized with ketamine hydrochloride and xylazine (100 and 2 mg / kg intramuscularly, respectively; Phoenix Scientific; St. Joseph, MO, and Moby; Shawnee, KS). Using the flat skull calibration function, a lateral ventricle (icv) guide catheter (PE-60, Clay Adams; Parsippany, NY) was placed stereotaxically (Model 900, David Kopf Instruments; Tujunga, CA) 1.0 mm posterior and anterior to bregma in the right hemisphere. 1.5 mm lateral to the bregma (see Wright et al.1985). The guide t...

Embodiment 3

[0259] Example 3: Development of Angiotensin IV Analogs as Hepatocyte Growth Factor / Met Modifiers

[0260] The 6-AH family of angiotensin IV analogues [D-Nle-X-Ile-NH-(CH 2 ) 5 -CONH 2 ; where X = various amino acids] can directly bind to hepatocyte growth factor (HGF) and inhibit the ability of HGF to form functional dimers. Metabolically stable 6-AH family member D-Nle-Tyr-Ile-NH-(CH 2 ) 5 -CONH 2 in the blood 1 / 2 time of 80 min, compared to the parent compound Norleual (Nle-Tyr-Leu-ψ-(CH 2 -NH 2 ) 3-4 -His-Pro-Phe, SEQ ID NO: 1) in blood t 1 / 2 The time is 3 The interaction of the H-hinge domain peptides results in a reduced ability of HGF to activate its receptor Met. This interference translates into inhibition of HGF-dependent signaling, proliferation and dispersion of concentrations in multiple cell types into the low picomolar range. We also noticed a significant correlation between 6-AH family members blocking HGF dimerization and inhibiting cellular activit...

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Abstract

Small molecule, peptidic hepatocyte growth factors mimics, which act as both mimetics and antagonists, have been generated. These molecules have been shown or predicted to have therapeutic potential for numerous pathologies including dementia, neurodegenerative disease, diabetes and metabolic syndrome, cancer, and defective wound healing.

Description

[0001] Federally Sponsored Research and Development Statement [0002] This invention was made in part with government support under Award No. MH086032 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention. [0003] sequence listing [0004] The present invention includes all the contents of the sequence listing in the attached TXT file "sequence.txt", which was created on April 2, 2012 and contains 1022 bytes, all of which are included herein by reference. [0005] manual [0006] Summarize technical field [0007] The present invention generally relates to the development of hepatocyte growth factor (HGF) mimetics, which can act as mimetics (agonists) or antagonists. The role of mimics: enhance cognitive function; act as a basic neuroprotective / neural regeneration factor; facilitate wound repair; improve insulin sensitivity and glucose transport; and reduce tissue or organ fibrosis to prevent or reverse dementia symptoms,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K38/18A61K38/17A61P25/28A61P3/10A61P35/00
CPCA61K38/00A61K38/06A61K38/07A61P1/16A61P3/10A61P9/00A61P9/10A61P11/00A61P13/12A61P17/00A61P25/00A61P25/28A61P27/02A61P35/00C07K5/021C07K5/0808A61K45/06C07K5/02
Inventor J·W·哈丁J·W·赖特C·C·伯努瓦L·H·卡瓦斯G·A·韦曼
Owner WASHINGTON STATE UNIVERSITY
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