Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats

• DOI: 10.1073/pnas.1520686113
• Publication Date: 2016-03-15T03:24:27Z
• Authors: Geraldine Harriman; Jeremy Greenwood; Sathesh Bhat; Xinyi Huang; Ruiying Wang; Debamita Paul; Liang Tong; Asish K. Saha; William F. Westlin; Rosana Kapeller; H. James Harwood
• Keywords: Male; 0301 basic medicine; 2. Zero hunger; Hep G2 Cells; Pyrimidinones; Thiophenes; Rats, Zucker; Fatty Liver; Molecular Docking Simulation; Rats, Sprague-Dawley; Structure-Activity Relationship; 03 medical and health sciences; Animals; Humans; Female; Obesity; Enzyme Inhibitors; Insulin Resistance; Protein Multimerization; Acetyl-CoA Carboxylase; Dyslipidemias

Significance Using structure-based drug design, we have identified a series of potent allosteric protein–protein interaction acetyl-CoA carboxylase inhibitors, exemplified by ND-630, that interact within the acetyl-CoA carboxylase subunit phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit enzymatic activity. ND-630 reduces fatty acid synthesis and stimulates fatty acid oxidation in cultured cells and experimental animals, reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia in diet-induced obese rats and reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c in Zucker diabetic fatty rats. These data suggest that ND-630 may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes, and fatty liver disease.