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Creation of an Anti-Inflammatory, Leptin-Dependent Anti-Obesity Celastrol Mimic with Better Druggability

Obesity is characterized by an excessive body mass, but is also closely associated with metabolic syndrome. And, so far, only limited pharmacological treatments are available for obesity management. Celastrol, a pentacyclic triterpenoid from a traditional Chinese medicine (Tripterygium wilfordii Hoo...

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Autores principales: Zhou, Bo, Yuan, Yaxia, Shi, Le, Hu, Sheng, Wang, Dong, Yang, Yang, Pan, Yuanhu, Kong, Dexin, Shikov, Alexander N., Duez, Pierre, Jin, Moonsoo, Li, Xiaohua, Hu, Xuebo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435713/
https://www.ncbi.nlm.nih.gov/pubmed/34526895
http://dx.doi.org/10.3389/fphar.2021.705252
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author Zhou, Bo
Yuan, Yaxia
Shi, Le
Hu, Sheng
Wang, Dong
Yang, Yang
Pan, Yuanhu
Kong, Dexin
Shikov, Alexander N.
Duez, Pierre
Jin, Moonsoo
Li, Xiaohua
Hu, Xuebo
author_facet Zhou, Bo
Yuan, Yaxia
Shi, Le
Hu, Sheng
Wang, Dong
Yang, Yang
Pan, Yuanhu
Kong, Dexin
Shikov, Alexander N.
Duez, Pierre
Jin, Moonsoo
Li, Xiaohua
Hu, Xuebo
author_sort Zhou, Bo
collection PubMed
description Obesity is characterized by an excessive body mass, but is also closely associated with metabolic syndrome. And, so far, only limited pharmacological treatments are available for obesity management. Celastrol, a pentacyclic triterpenoid from a traditional Chinese medicine (Tripterygium wilfordii Hook.f.), has shown remarkable potency against obesity, inflammation and cancer, but its high toxicity, low natural abundance and tedious chemical synthesis hindered its translation into clinics. In the present work, a triterpenoid library was screened for compounds with both high natural abundance and structural similarity to celastrol; from this library, glycyrrhetinic acid (GA), a compound present in extremely high yields in Glycyrrhiza uralensis Fisch. ex DC., was selected as a possible scaffold for a celastrol mimic active against obesity. A simple chemical modification of GA resulted in GA-02, a derivative that suppressed 68% of food intake in diet-induced obesity mice and led to 26.4% weight loss in 2 weeks. GA-02 plays a role in obesity treatment by re-activating leptin signaling and reducing systemic and, more importantly, hypothalamic inflammation. GA-02 was readily bioavailable with unnoticeable in vitro and in vivo toxicities. The strategy of scaffold search and modification on the basis of bio-content and structural similarity has proved to be a green, economic, efficient and practical way of widening the medicinal applications of “imperfect” bioactive natural compounds.
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spelling pubmed-84357132021-09-14 Creation of an Anti-Inflammatory, Leptin-Dependent Anti-Obesity Celastrol Mimic with Better Druggability Zhou, Bo Yuan, Yaxia Shi, Le Hu, Sheng Wang, Dong Yang, Yang Pan, Yuanhu Kong, Dexin Shikov, Alexander N. Duez, Pierre Jin, Moonsoo Li, Xiaohua Hu, Xuebo Front Pharmacol Pharmacology Obesity is characterized by an excessive body mass, but is also closely associated with metabolic syndrome. And, so far, only limited pharmacological treatments are available for obesity management. Celastrol, a pentacyclic triterpenoid from a traditional Chinese medicine (Tripterygium wilfordii Hook.f.), has shown remarkable potency against obesity, inflammation and cancer, but its high toxicity, low natural abundance and tedious chemical synthesis hindered its translation into clinics. In the present work, a triterpenoid library was screened for compounds with both high natural abundance and structural similarity to celastrol; from this library, glycyrrhetinic acid (GA), a compound present in extremely high yields in Glycyrrhiza uralensis Fisch. ex DC., was selected as a possible scaffold for a celastrol mimic active against obesity. A simple chemical modification of GA resulted in GA-02, a derivative that suppressed 68% of food intake in diet-induced obesity mice and led to 26.4% weight loss in 2 weeks. GA-02 plays a role in obesity treatment by re-activating leptin signaling and reducing systemic and, more importantly, hypothalamic inflammation. GA-02 was readily bioavailable with unnoticeable in vitro and in vivo toxicities. The strategy of scaffold search and modification on the basis of bio-content and structural similarity has proved to be a green, economic, efficient and practical way of widening the medicinal applications of “imperfect” bioactive natural compounds. Frontiers Media S.A. 2021-08-30 /pmc/articles/PMC8435713/ /pubmed/34526895 http://dx.doi.org/10.3389/fphar.2021.705252 Text en Copyright © 2021 Zhou, Yuan, Shi, Hu, Wang, Yang, Pan, Kong, Shikov, Duez, Jin, Li and Hu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Zhou, Bo
Yuan, Yaxia
Shi, Le
Hu, Sheng
Wang, Dong
Yang, Yang
Pan, Yuanhu
Kong, Dexin
Shikov, Alexander N.
Duez, Pierre
Jin, Moonsoo
Li, Xiaohua
Hu, Xuebo
Creation of an Anti-Inflammatory, Leptin-Dependent Anti-Obesity Celastrol Mimic with Better Druggability
title Creation of an Anti-Inflammatory, Leptin-Dependent Anti-Obesity Celastrol Mimic with Better Druggability
title_full Creation of an Anti-Inflammatory, Leptin-Dependent Anti-Obesity Celastrol Mimic with Better Druggability
title_fullStr Creation of an Anti-Inflammatory, Leptin-Dependent Anti-Obesity Celastrol Mimic with Better Druggability
title_full_unstemmed Creation of an Anti-Inflammatory, Leptin-Dependent Anti-Obesity Celastrol Mimic with Better Druggability
title_short Creation of an Anti-Inflammatory, Leptin-Dependent Anti-Obesity Celastrol Mimic with Better Druggability
title_sort creation of an anti-inflammatory, leptin-dependent anti-obesity celastrol mimic with better druggability
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435713/
https://www.ncbi.nlm.nih.gov/pubmed/34526895
http://dx.doi.org/10.3389/fphar.2021.705252
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