A new drug screening technology to identify new potential anti-diabetes compounds was developed by researchers at Harvard T.H. Chan School of Public Health, USA. The research, entitled “Phenotypic assays identify azoramide a small molecule modulator of the unfolded protein response with anti-diabetic activity,” was published this June in Science Translational Medicine.
This new drug screening technology enables researchers to directly examine the function of an organelle called the endoplasmic reticulum (ER) in live cellular systems in culture at the laboratory. The endoplasmic reticulum has a crucial role in protein, lipid, and glucose metabolism as well as cellular calcium signaling and homeostasis. Alterations of ER function and induction of chronic ER stress are linked with many clinical conditions ranging from diabetes and neurodegenerative diseases to cancer and inflammation.
In an obese individual, the organelle ER in metabolic tissues like the liver and fat does not function appropriately and is not able to deal with the high production of proteins and lipids. As a result, in obesity the ER stress is induced and contributes to cellular dysfunction and for the development of insulin resistance. In insulin resistance, the body has some difficulty in metabolizing glucose, leading to high blood sugar and ultimately to the development of type 2 Diabetes as well as a series of other cellular dysfunctions that can lead to heart and blood vessel damage.
Gökhan S. Hotamisligil, senior author of the study, said in the news release that although they and others have contributed for the discovered of the role of ER stress in the development of diabetes and metabolic disease the translation of that understanding into efficient strategies to restore ER function have been until now limited.
With this screening system, the researchers were able to quantify the number of chaperone molecules that control and promote ER function, as well as the capacity of the ER to fold proteins into their three-dimensional conformations. They characterized a small-molecule compound, named azoramide, which improves ER protein-folding ability and activates ER chaperone capacity to protect cells against ER stress in several systems. The azoramide also showed a strong anti-diabetic efficacy in mouse models of obesity and type 2 Diabetes by improving insulin sensitivity, i.e. the ability of peripheral tissues to sense insulin, and pancreatic β cell function by improving insulin production.
This technology is a potent method to test other potential molecules with positive effect on critical molecular pathways central to diseases from diabetes to retinitis pigmentosa, cystic fibrosis, Huntington’s disease and Alzheimer’s where ER dysfunction is also implicated. The follow-up of this study will be to evaluate this or others compounds into human clinical trials.