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

Abstract

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.

A terpenoids database with the chemical content as a novel agronomic trait

“…Structural similarity is one of the key strategies for drug discovery ( 44 ). Higher-content compounds that are structurally similar to other high-value compounds have the modification potential to wider applications ( 24 ).…”

“…Similarly, Bellis sylvestris (nomenclature family: Asteraceae , order: Asterales , class: Magnoliopsida ) and Gypsophila oldhamiana (nomenclature family: Caryophyllaceae , order: Caryophyllales , class Magnoliopsida ), despite having a distant taxonomic relationship, both produce very similar chemicals ( Table 1 ). Using information as such, we were able to identify alternatives to celastrol that exhibit improved drug-like properties, along with increased availability and reduced toxicity ( 24 ).…”

“…Unrelated plants may evolve the same natural products or different compounds with functionally similar properties, due to environmental stress involving genetic changes ( 21–23 ). Taking advantage of the considerable difference in the abundances of structurally similar compounds, a low-content natural product can be substituted with another compound that shares similar functions but can be obtained in higher yields from the original plant ( 24 ).…”

The licorice metabolite enoxolone attenuates Clostridioides difficile pathophysiology by corrupting its metabolic and toxin production networks

“…Weight loss was also evident in the enoxolone/vancomycin combination group, when compared to mice that were only given vancomycin ( Figure 3D ). We speculate that the observed increased weight loss was a side effect of enoxolone, as the compound is reported to cause hypertension and an analog was shown to suppress food intake (26). Analysis of spore and toxin loads revealed there was no significant difference in spore bioburdens ( Figure 3E ), but the fecal toxin titers of enoxolone treated mice were ∼1 log less than mice given the vehicle ( Figure 3G ).…”