A. Fernandez-gamba, M. C. Leal, L. Morelli, and E. M. Castano, Insulindegrading enzyme: structure-function relationship and its possible roles in health and disease, Curr. Pharm. Des, vol.15, pp.3644-3655, 2009.

L. B. Hersh, The insulysin (insulin degrading enzyme) enigma, Cell. Mol. Life Sci, vol.63, pp.2432-2434, 2006.

I. V. Kurochkin and S. Goto, Alzheimer's beta-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme, FEBS Lett, vol.345, pp.33-37, 1994.

Q. Guo, M. Manolopoulou, Y. Bian, A. B. Schilling, and W. Tang, Molecular basis for the recognition and cleavages of IGF-II, TGF-[alpha], and amylin by human insulin-degrading enzyme, J. Mol. Biol, vol.395, pp.430-443, 2010.

F. Authier, P. H. Cameron, C. Merlen, M. Kouach, and G. Briand, Endosomal proteolysis of glucagon at neutral pH generates the bioactive degradation product miniglucagon-(19-29), Endocrinology, vol.144, pp.5353-5364, 2003.

R. G. Bennett, F. G. Hamel, and W. C. Duckworth, An insulin-degrading enzyme inhibitor decreases amylin degradation, increases amylin-induced cytotoxicity, and increases amyloid formation in insulinoma cell cultures, Diabetes, vol.52, pp.2315-2320, 2003.

C. Ciaccio, Somatostatin: a novel substrate and a modulator of insulindegrading enzyme activity, J. Mol. Biol, vol.385, pp.1556-1567, 2009.

I. V. Kurochkin, Amyloidogenic determinant as a substrate recognition motif of insulin-degrading enzyme, FEBS Lett, vol.427, pp.153-156, 1998.

Y. Shen, A. Joachimiak, M. R. Rosner, and W. J. Tang, Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism, Nature, vol.443, pp.870-874, 2006.

E. Malito, R. Hulse, and W. J. Tang, Amyloid b-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysin, Cell. Mol. Life Sci, vol.65, pp.2574-2585, 2008.

K. Glebov, S. Schütze, and J. Walter, Functional relevance of a novel SlyX motif in non-conventional secretion of insulin-degrading enzyme, J. Biol. Chem, vol.286, pp.22711-22715, 2011.

R. G. Bennett, J. Fawcett, M. C. Kruer, W. C. Duckworth, and F. G. Hamel, Insulin inhibition of the proteasome is dependent on degradation of insulin by insulin-degrading enzyme, J. Endocrinol, vol.177, pp.399-405, 2003.

C. L. Epting, Stem cell antigen-1 localizes to lipid microdomains and associates with insulin degrading enzyme in skeletal myoblasts, J. Cell. Physiol, vol.217, pp.250-260, 2008.

C. Beuzelin, Deletion of the fission yeast homologue of human insulinase reveals a TORC1-dependent pathway mediating resistance to proteotoxic stress, PLoS ONE, vol.8, p.67705, 2013.

M. B. De-tullio, Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic Ab peptide aggregates, PLoS ONE, vol.8, p.59113, 2013.

I. A. Mirsky and G. Perisutti, Effect of insulinase-inhibitor on hypoglycemic action of insulin, Science, vol.122, pp.559-560, 1955.

J. Galli, Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat, Nat. Genet, vol.12, pp.31-37, 1996.

H. Fakhrai-rad, Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats, Hum. Mol. Genet, vol.9, pp.2149-2158, 2000.

W. Farris, Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein, Am. J. Pathol, vol.164, pp.1425-1434, 2004.

W. Farris, Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo, Proc. Natl Acad. Sci. USA, vol.100, pp.4162-4167, 2003.

S. O. Abdul-hay, Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance, PLoS ONE, vol.6, p.20818, 2012.

M. A. Leissring, Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin, PLoS ONE, vol.5, p.10504, 2010.

S. O. Abdul-hay, Optimization of peptide hydroxamate inhibitors of insulin-degrading enzyme reveals marked substrate-selectivity, J. Med. Chem, vol.56, pp.2246-2255, 2013.

J. P. Maianti, Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones, Nature, vol.511, pp.94-98, 2014.

X. Hu and R. Manetsch, Kinetic target-guided synthesis, Chem. Soc. Rev, vol.39, pp.1316-1324, 2010.

W. G. Lewis, Click chemistry in situ: acetylcholinesterase as a reaction vessel for the selective assembly of a femtomolar inhibitor from an array of building blocks, Angew. Chem. Int. Ed. Engl, vol.41, pp.1053-1057, 2002.

R. Manetsch, In situ click chemistry: enzyme inhibitors made to their own specifications, J. Am. Chem. Soc, vol.126, pp.12809-12818, 2004.

V. P. Mocharla, In situ click chemistry: enzyme-generated inhibitors of carbonic anhydrase II, Angew. Chem. Int. Ed. Engl, vol.44, p.116, 2005.

M. Whiting, Inhibitors of HIV-1 protease by using in situ click chemistry, Angew. Chem. Int. Ed. Engl, vol.45, pp.1435-1439, 2006.

T. Hirose, Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry, J. Antibiot, vol.62, p.277, 2009.

N. Willand, Exploring drug target flexibility using in situ click chemistry: application to a mycobacterial transcriptional regulator, ACS Chem. Biol, vol.5, pp.1007-1013, 2010.

J. Charton, Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-b hydrolysis, Eur. J. Med. Chem, vol.79, pp.184-193, 2014.

J. K. Lau, Absolute potassium cation affinities (PCAs) in the gas phase, Chemistry, vol.9, p.3383, 2003.

R. D. Brown, B. A. Coller, and J. E. Kent, 4-oxadiazoles: a theoretical study of electric dipole moments, Theor. Chim. Acta, vol.2, pp.435-446, 1968.

L. A. Mccord, Conformational states and recognition of amyloidogenic peptides of human insulin-degrading enzyme, Proc. Natl Acad. Sci. USA, vol.110, pp.13827-13832, 2013.

M. Flipo, Hydroxamates: relationships between structure and plasma stability, J. Med. Chem, vol.52, pp.6790-6802, 2009.

W. Q. Qiu, Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation, J. Biol. Chem, vol.273, pp.32730-32738, 1998.

D. Edbauer, M. Willem, S. Lammich, H. Steiner, and C. Haass, Insulindegrading enzyme rapidly removes the b-amyloid precursor protein intracellular domain (AICD), J. Biol. Chem, vol.277, pp.13389-13393, 2002.

M. Manolopoulou, Q. Guo, E. Malito, A. B. Schilling, and W. J. Tang, Molecular basis of catalytic chamber-assisted unfolding and cleavage of human insulin by human insulin-degrading enzyme, J. Biol. Chem, vol.284, pp.14177-14188, 2009.

Z. Otwinowski and W. Minor, Processing of X-ray diffraction data collected in oscillation mode, Methods Enzymol, vol.276, pp.307-326, 1997.

E. Potterton, S. Mcnicholas, E. Krissinel, K. Cowtan, and M. Noble, The CCP4 molecular-graphics project, Acta Crystallogr. D Biol. Crystallogr, vol.58, pp.1955-1957, 2002.

P. Emsley and K. Cowtan, Coot: model-building tools for molecular graphics, Acta Crystallogr. D Biol. Crystallogr, vol.60, pp.2126-2132, 2004.

P. D. Adams, PHENIX: a comprehensive Python-based system for macromolecular structure solution, Acta Crystallogr. D, vol.66, pp.213-221, 2010.

D. Svergun, Determination of the regularization parameter in indirecttransform methods using perceptual criteria, J. Appl. Cryst, vol.25, pp.495-503, 1992.

D. Svergun, C. Barbareto, and G. Koch, CRYSOL-a program to evaluate X-ray solution scattering of biological macromolecules from atomic coordinates, J. Appl. Cryst, vol.28, pp.768-773, 1995.

D. B. , G. B. , T. V. , M. G. , J. J. Synthesized-compounds et al., performed the pharmacokinetic study in mice, NH, EW performed ITT, OGTT IPGTT in C57Bl6 mice, EE performed the pharmacodynamic study in OGTT in C57BL/6 and NOD both WT and Ide À / À , and the GSIS experiments