Synthesis and preclinical testing of a selective beta-subtype agonist of thyroid hormone receptor ZTA-261.
Journal
Communications medicine
ISSN: 2730-664X
Titre abrégé: Commun Med (Lond)
Pays: England
ID NLM: 9918250414506676
Informations de publication
Date de publication:
06 Aug 2024
06 Aug 2024
Historique:
received:
21
12
2022
accepted:
04
07
2024
medline:
7
8
2024
pubmed:
7
8
2024
entrez:
6
8
2024
Statut:
epublish
Résumé
Thyroid hormones (TH) regulate the basal metabolic rate through their receptors THRα and THRβ. TH activates lipid metabolism via THRβ, however, an excess amount of TH can lead to tachycardia, bone loss, and muscle wasting through THRα. In recent years, TH analogs that selectively bind to THRβ have gained attention as new agents for treating dyslipidemia and obesity, which continue to pose major challenges to public health worldwide. We developed a TH analog, ZTA-261, by modifying the existing THRβ-selective agonists GC-1 and GC-24. To determine the THRβ-selectivity of ZTA-261, an in vitro radiolabeled TH displacement assay was conducted. ZTA-261 was intraperitoneally injected into a mouse model of high-fat diet-induced obesity, and its effectiveness in reducing body weight and visceral fat, and improving lipid metabolism was assessed. In addition, its toxicity in the liver, heart, and bone was evaluated. ZTA-261 is more selective towards THRβ than GC-1. Although ZTA-261 is less effective in reducing body weight and visceral fat than GC-1, it is as effective as GC-1 in reducing the levels of serum and liver lipids. These effects are mediated by the same pathway as that of T ZTA-261, a highly selective and less toxic THRβ agonist, has the potential to be used as a drug for treating diseases related to lipid metabolism. Nearly 10% of the world’s population suffers from obesity or is overweight. These conditions are closely related to disorders of lipid metabolism, posing significant challenges to individuals and healthcare systems. Thyroid hormone (TH) activates metabolism by binding to specific protein partners, called TH receptors (THRs). There are two types of THRs, THRα and THRβ. THRβ activates lipid metabolism; however, THRα negatively affects the heart, bone, and muscle when TH is in excess. This study developed a drug called ZTA-261 that selectively binds to THRβ. Its administration to mice with induced obesity from a high-fat diet resulted in reduced body fat without any apparent toxicity. Therefore, ZTA-261 is a promising candidate to improve lipid metabolism and address the obesity epidemic.
Sections du résumé
BACKGROUND
BACKGROUND
Thyroid hormones (TH) regulate the basal metabolic rate through their receptors THRα and THRβ. TH activates lipid metabolism via THRβ, however, an excess amount of TH can lead to tachycardia, bone loss, and muscle wasting through THRα. In recent years, TH analogs that selectively bind to THRβ have gained attention as new agents for treating dyslipidemia and obesity, which continue to pose major challenges to public health worldwide.
METHODS
METHODS
We developed a TH analog, ZTA-261, by modifying the existing THRβ-selective agonists GC-1 and GC-24. To determine the THRβ-selectivity of ZTA-261, an in vitro radiolabeled TH displacement assay was conducted. ZTA-261 was intraperitoneally injected into a mouse model of high-fat diet-induced obesity, and its effectiveness in reducing body weight and visceral fat, and improving lipid metabolism was assessed. In addition, its toxicity in the liver, heart, and bone was evaluated.
RESULTS
RESULTS
ZTA-261 is more selective towards THRβ than GC-1. Although ZTA-261 is less effective in reducing body weight and visceral fat than GC-1, it is as effective as GC-1 in reducing the levels of serum and liver lipids. These effects are mediated by the same pathway as that of T
CONCLUSIONS
CONCLUSIONS
ZTA-261, a highly selective and less toxic THRβ agonist, has the potential to be used as a drug for treating diseases related to lipid metabolism.
Nearly 10% of the world’s population suffers from obesity or is overweight. These conditions are closely related to disorders of lipid metabolism, posing significant challenges to individuals and healthcare systems. Thyroid hormone (TH) activates metabolism by binding to specific protein partners, called TH receptors (THRs). There are two types of THRs, THRα and THRβ. THRβ activates lipid metabolism; however, THRα negatively affects the heart, bone, and muscle when TH is in excess. This study developed a drug called ZTA-261 that selectively binds to THRβ. Its administration to mice with induced obesity from a high-fat diet resulted in reduced body fat without any apparent toxicity. Therefore, ZTA-261 is a promising candidate to improve lipid metabolism and address the obesity epidemic.
Autres résumés
Type: plain-language-summary
(eng)
Nearly 10% of the world’s population suffers from obesity or is overweight. These conditions are closely related to disorders of lipid metabolism, posing significant challenges to individuals and healthcare systems. Thyroid hormone (TH) activates metabolism by binding to specific protein partners, called TH receptors (THRs). There are two types of THRs, THRα and THRβ. THRβ activates lipid metabolism; however, THRα negatively affects the heart, bone, and muscle when TH is in excess. This study developed a drug called ZTA-261 that selectively binds to THRβ. Its administration to mice with induced obesity from a high-fat diet resulted in reduced body fat without any apparent toxicity. Therefore, ZTA-261 is a promising candidate to improve lipid metabolism and address the obesity epidemic.
Identifiants
pubmed: 39107484
doi: 10.1038/s43856-024-00574-z
pii: 10.1038/s43856-024-00574-z
doi:
Types de publication
Journal Article
Langues
eng
Pagination
152Subventions
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP19H03178
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP24H00058
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP19H05643
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP26000013
Informations de copyright
© 2024. The Author(s).
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