Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes1,2, and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene3,4, 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 dysfunction5,6. 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. 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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Protein Data Bank
The coordinates and the structure factors of the IDE·6b complex have been deposited in the Protein Data Bank under the accession code 4LTE.
This research was supported by NIH/NIGMS (R01 GM065865 (D.R.L.), R00 GM080097 (M.A.S.), R01 GM81539 (W.-J.T.), T32 GM008444 (Z.H.F.), F30 CA174152 (Z.H.F.), DP2 OD002374 (A.S.)), Howard Hughes Medical Institute (D.R.L.), Diabetes and Cancer Centers of Albert Einstein College of Medicine (M.J.C.), American Diabetes Association no. 7-11-CD-06 (M.A.L.), Burroughs Wellcome Fund CABS (A.S.), and the Searle Scholars Program (A.S.). The Fonds de Recherche en Santé du Québec (FRSQ) and the Alfred Bader Fund supported J.P.M. We thank C. Russ and H. Spurling (Broad Institute) and C. Daly (FAS Center for Systems Biology) for DNA sequencing assistance. We are grateful to S. Johnston and C. Mosher (Broad Institute) for 6bK stability measurements. W. Nolte provided mouse IDE, L. McCord purified CF-IDE and Y.-G. Kim performed CGRP cleavage assays. We are grateful to A. Badran, E. Homan, A. M. Lone and M. Leidl (Harvard University) for experimental assistance. We thank B. Kahn and N. Gray for discussions.
Extended data figures
The IDE domains 1, 2, 3, and 4 are colored green, blue, yellow, and red, respectively (2.7 Å resolution, pdb: 4LTE). Macrocycle 6b is represented as a ball-and-stick model, and the catalytic zinc atom is represented as an orange sphere. The macrocycle 6b is seen interacting within a 10 Å-deep hydrophobic pocket. The p-benzoyl-phenylalanine is shown in red, the cyclohexylalanine in blue, the fumarate linker in grey, and the D-lysine backbone in purple. The final scene shows a superimposition of 6b (shown as a surface rendering) on the co-crystal structure of insulin (shown in orange) within the IDE cavity (pdb: 2WBY), demonstrating that 6b binding to IDE is predicted to preclude substrate binding.
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