Methods and systems for modulating hormones and related methods, agents and compositions
Inventors
Goddard, III, William A. • MENNA, Mark • PANDOL, Stephen • Abrol, Ravinder
Assignees
California Institute of Technology • US Department of Veterans Affairs • University of California San Diego UCSD
Publication Number
US-10330678-B2
Publication Date
2019-06-25
Expiration Date
2031-06-17
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Abstract
Provided herein are bitter taste receptor ligands, related agents, combinations, compositions, methods and systems for modulating release of a metabolic hormone in vitro and in vivo from cells of the GI tract of an individual.
Core Innovation
The invention provides methods, systems, and compositions for modulating the release of metabolic hormones from cells of the gastrointestinal (GI) tract by administering one or more ligands that bind to specific GI bitter taste receptors. In particular, bitter taste receptor ligands such as 6-n-Propylthiouracil (PTU), Phenylthiocarbamide (PTC), denatonium benzoate, and derivatives thereof are used to modulate the release of metabolic hormones including glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and cholecystokinin (CCK). These ligands bind to GI bitter taste receptors such as TAS2R38 and TAS2R47, triggering receptor conformational changes that alter hormone release and related biological processes.
The problem addressed is the challenge in controlling and modulating hormone production, especially metabolic hormone release, to treat various conditions in an individual. While metabolic hormones regulate metabolism networks within cells and organs, effective methods to modulate their release in vivo and in vitro had not been adequately developed. The invention solves this by providing bitter taste receptor ligands, related agents, and compositions that target GI bitter taste receptors to directly modulate hormone secretion and treat metabolic-related conditions.
The invention also addresses minimizing systemic absorption of the bitter taste receptor ligands by conjugating them with complementary molecules such as polysaccharides (e.g., cellulose) or polyethylene glycol (PEG). This conjugation helps localize the ligand's activity within the GI tract, increasing specificity and reducing adverse effects. Further, the invention includes methods for structure prediction of bitter taste receptors and screening candidate ligands to identify effective modulators of hormone release. Applications extend to treatment or prevention of metabolic diseases including obesity and diabetes by modulating hormone release from endocrine cells expressing GI bitter taste receptors.
Claims Coverage
The claims include one independent claim focused on a method of modulating hormone release using a conjugated GI bitter taste receptor ligand, comprising several inventive features related to ligand design, conjugation, and hormone modulation.
Method of modulating hormone release using conjugated GI bitter taste receptor ligand
A method comprising contacting a specific conformation of a GI bitter taste receptor comprising TAS2R38 in a cell with a GI bitter taste receptor ligand comprising 6-n-Propylthiouracil (PTU) that is conjugated to a complementary molecule which interferes with systemic absorption of the ligand, thereby modulating an increase or decrease of a metabolic hormone selected from GLP-1, PYY, and CCK through binding of the receptor ligand.
Targeting endocrine cells expressing GI bitter taste receptors
The method wherein the cell contacted is an endocrine cell, including specific subtypes such as L-cells, I-cells, or K-cells, which are responsible for releasing metabolic hormones upon receptor activation.
Use of complementary molecules to minimize systemic absorption
The complementary molecule conjugated to PTU is selected from the group consisting of nucleic acids, proteins, polyethylene glycol (PEG), monosaccharides, oligosaccharides, and polysaccharides; with cellulose being specifically exemplified as a complementary molecule.
The claimed invention covers a method of modulating release of metabolic hormones by administering to endocrine cells a GI bitter taste receptor ligand (PTU) conjugated to a complementary molecule that reduces systemic absorption, thereby targeting receptor TAS2R38 and modulating hormones GLP-1, PYY, and CCK. The claims emphasize the ligand conjugation strategy and specific receptor and cell targets involved in hormone release modulation.
Stated Advantages
Allows modulation of GI bitter taste receptor activity to control secretion and systemic release of metabolic hormones.
Provides a means to treat or prevent metabolic diseases such as obesity and diabetes through hormone release modulation.
Minimizes systemic absorption of bitter taste receptor ligands, increasing specificity of action and reducing adverse effects.
Enables targeted delivery of bitter taste receptor ligands to specific GI tract locations and cell types to optimize hormone modulation.
Documented Applications
Treatment or prevention of metabolic conditions including obesity, diabetes, liver diseases, and cardiovascular diseases by modulating release of metabolic hormones GLP-1, PYY, and CCK.
Use in medical, biological analysis, food processing, taste/flavor modulation, nutrition, nutraceutical applications, and diagnostic clinical applications involving modulation of GI and intestinal bitter taste receptor activity.
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