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Potential anti-obesity effects of a long-acting cocaine hydrolase
Xirong Zheng1, Jing Deng1, Ting Zhang1
1Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
Abstract:
A long-acting cocaine hydrolase, known as CocH3-Fc(M3), engineered from human butyrylcholinesterase (BChE) was tested, in this study, for its potential anti-obesity effects. Mice on a high-fat diet gained significantly less body weight when treated weekly with 1 mg/kg CocH3-Fc(M3) compared to control mice, though their food intake was similar. There is no correlation between the average body weight and the average food intake, which is consistent with the previously reported observation in BChE knockout mice. In addition, molecular modeling was carried out to understand how ghrelin binds with CocH3, showing that ghrelin binds with CocH3 in a similar mode as ghrelin binding with wild-type human BChE. The similar binding structures explains why CocH3 and BChE have similar catalytic activity against ghrelin.
Insights
A novel enzyme, CocH3-Fc(M3), engineered from human butyrylcholinesterase, demonstrated anti-obesity effects in mice by reducing weight gain without affecting food intake. This suggests a potential therapeutic avenue for obesity management.
Area of Science:
- Biochemistry
- Pharmacology
- Metabolic research
Background:
- Obesity is a complex metabolic disorder with significant health implications.
- Human butyrylcholinesterase (BChE) is an enzyme with potential therapeutic applications.
- Engineered enzymes offer novel strategies for treating metabolic diseases.
Purpose of the Study:
- To evaluate the anti-obesity effects of a long-acting cocaine hydrolase, CocH3-Fc(M3), engineered from BChE.
- To investigate the mechanism underlying the potential anti-obesity effects of CocH3-Fc(M3).
Main Methods:
- Administration of CocH3-Fc(M3) to mice on a high-fat diet.
- Monitoring body weight and food intake in treated and control groups.
- Molecular modeling to study ghrelin binding to CocH3 and wild-type BChE.
Main Results:
- Mice treated with CocH3-Fc(M3) exhibited significantly reduced body weight gain compared to controls.
- Food intake remained similar between treated and control groups, indicating no direct correlation with weight loss.
- Molecular modeling revealed similar binding modes of ghrelin to CocH3 and wild-type BChE.
Conclusions:
- CocH3-Fc(M3) demonstrates significant anti-obesity potential by reducing weight gain independently of food intake.
- The enzyme's mechanism may involve interactions similar to those of BChE with ghrelin.
- Further research into CocH3-Fc(M3) could lead to new obesity treatments.