Characterization of Protein-Metabolite and Protein-Substrate Interactions of Disease Genes

Discovery of protein-metabolite and protein-substrate interactions that can specifically regulate genes involved in human biology is an important pursuit, as the study of such interactions can expand our understanding of human physiology and reveal novel therapeutic targets. The identification and characterization of these interactions can be approached from different perspectives. Chemists often use bioactive small molecules, such as natural products or synthetic compounds, as probes to identify therapeutically relevant protein targets. Biochemists and biologists often begin with a specific protein and seek to identify the endogenous ligands that bind to it. These interests have led to the development of methodology that relies heavily on synthetic and analytical chemistry to identify interactions, an approach that is complemented by in vivo strategies for validating the biological consequences of specific interactions

Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones

Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes, and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene, the relationship between the activity of the zinc metalloprotein IDE and glucose homeostasis remains unclear. Although Ide −/− mice have elevated insulin levels, they exhibit impaired, rather than improved, glucose tolerance that may arise from compensatory insulin signalling dysfunction. IDE inhibitors that are active in vivo are therefore needed to elucidate IDE’s physiological roles and to determine its potential to serve as a target for the treatment ofdiabetes. Here we report the discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. An X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity. Treatment of lean and obese mice with this inhibitor shows that IDE regulates the abundance and signalling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that augment insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying. These findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type-2 diabetes and expand our understanding of the roles of IDE in glucose and hormone regulation.Chemistry and Chemical Biolog

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xvi, 397 p. : il.; 24 cm