Sortilin-Binding Small Molecules for Increasing Glucose Uptake

a technology of small molecules and sortilin, which is applied in the field of sortilin-binding small molecules for increasing glucose uptake, can solve problems such as glucose transport d

Inactive Publication Date: 2016-11-17
UNIV OF SOUTH FLORIDA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Morbidly obese mice have decreased sortilin whi

Method used

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  • Sortilin-Binding Small Molecules for Increasing Glucose Uptake
  • Sortilin-Binding Small Molecules for Increasing Glucose Uptake
  • Sortilin-Binding Small Molecules for Increasing Glucose Uptake

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Embodiment Construction

[0018]Embodiments of the invention are directed to compounds with the ability to dock at a site within sortilin to promote the increase of glucose uptake. The compounds are identified by their ability to suitably bind to a region of the sortilin protein with high affinity and thereby mediate the interaction of sortilin with various protein molecules or other natural substrates. Compounds of three scaffolds, according to embodiments of the invention, bind to sortilin both in vivo and in silico.

[0019]Sortilin is alternatively spliced, to generate two splice variants in humans. Exon 17b, is a pseudoexon, which is absent in sortilin WT. Inclusion of this exon via alternative splicing generates a transcript with an extra coding exon between VSP10 and transmembrane domains. In neurons, downregulation of TDP-43 as seen in frontotemporal lobal degeneration, causes an increase in splice variant Sortilin 17b. It appears that splice variant sortilin 17b can bind to the sortilin ligand but is u...

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Abstract

Various scaffolds of small molecules capable of binding to the active site of sortilin are identified by in silico methods. These scaffolds include norbornene anhydride amino acid adducts, phenyl-amide-acids of benzyl substituted glutaric acids, and 2-substituted 3-oxo-1,2,3,4-tetrahydro-2-quinoxalines. These sortilin ligands increase the uptake of glucose in 3T3L1 cells and can be employed in compositions to increase uptake of glucose for the treatment of diabetic patents.

Description

CROSS-REFERENCE TO A RELATED APPLICATION[0001]This application claims the benefit of U.S. Provisional Application Ser. No. 62 / 160,220, filed May 12, 2015, the disclosure of which is hereby incorporated by reference in its entirety, including all figures, tables and drawings.[0002]This invention was made with government support under VAMR 821-MR-EN-20606 awarded by Veteran Affairs. The government has certain rights in the invention.BACKGROUND OF INVENTION[0003]Sortilin, which is generated from sortilin WT transcript, is highly conserved across species. It has an endoplasmic reticulum (ER) import signal, a vacuolar protein sorting 10 (VSP10) luminal domain, a transmembrane domain and a cytosolic domain. Sortilin ligands bind to the VSP10 domain while the cytosolic domain contains the active sorting signal that directs sortilin and its ligands to lysosomes. Protease cleavage within the extracellular stalk of sortilin releases the sortilin ectodomain by an event called shedding. Sortili...

Claims

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Application Information

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IPC IPC(8): A61K31/498A61K31/197C40B30/02A61K31/403G16C20/64
CPCA61K31/498C40B30/02A61K31/197A61K31/403A61K38/00A61K31/4035G16B35/00G16C20/60G16C20/64A61P3/10
Inventor PATEL, NIKETA A.SPARKS, ROBERT PLEASANTSGUIDA, WAYNE CHARLES
Owner UNIV OF SOUTH FLORIDA
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