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Maianti, Juan

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Maianti

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Juan

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Maianti, Juan
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    Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones
    (Nature Publishing Group, 2014) Maianti, Juan; McFedries, Amanda; Foda, Zachariah H.; Kleiner, Ralph; Du, Xiu Quan; Leissring, Malcolm A.; Tang, Wei-Jen; Charron, Maureen J.; Seeliger, Markus A.; Saghatelian, Alan; Liu, David
    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.
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    Therapeutic potential and physiological roles of Insulin-Degrading Enzyme illuminated by a DNA-templated macrocyclic inhibitor
    (2015-05-19) Maianti, Juan; Liu, David R.; Saghatelian, Alan; Gray, Nathanael S.
    Insulin-Degrading Enzyme (IDE) is a zinc-metalloprotease responsible for the clearance of insulin in peripheral tissues. Despite decades of speculation that inhibiting endogenous insulin degradation might treat Type-2 Diabetes, the functional relationship between IDE and glucose homeostasis remains unclear. 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 of diabetes. In this thesis I describe the development of the first highly specific IDE in vivo probe, identified from a DNA-templated library of macrocycles, which enabled the first study of the physiological consequences of IDE inhibition. An X-ray structure of the macrocycle bound to IDE reveals that it engages a novel binding pocket away from the catalytic site, which explains its remarkable specificity and its suitability to study IDE in vivo. Treatment of lean and obese mice with this inhibitor revealed that IDE regulates multiple metabolic hormones, including glucagon and amylin, in addition to insulin. Under physiological conditions that mimic a meal, such as oral glucose administration, acute IDE inhibition leads to substantial improvement in glucose tolerance, owing to the potentiation of endogenous insulin and amylin levels over glucagon signaling. These studies demonstrated the feasibility of modulating IDE activity as a therapeutic strategy to treat diabetes and expanded our understanding of the roles of IDE in glucose and hormone regulation. Based on these studies we sought to develop substrate-selective inhibitors that block IDE’s ability to degrade insulin but not its ability to degrade glucagon, which would represent a major step forward towards IDE-targeted therapeutics. The first-generation DNA-templated inhibitor was retailored into a fluorescent anisotropy tool for high-throughput screening of diverse small-molecule libraries. We discovered and characterized a family of IDE inhibitors with sub-micromolar potencies that inherited the remarkable specificity for IDE over other metalloproteases, and selectively obstruct IDE-mediated insulin degradation in a way that accommodates for glucagon cleavage. In conclusion, these findings offer new insights into the biological roles of IDE and establish a novel strategy to selectively potentiate the physiological insulin response in order to improve blood sugar control in Type-2 Diabetes.