Insulin-degrading Enzyme Inhibitors Research Articles

Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules

DNA-encoded libraries have emerged as a widely used resource for discovery of bioactive small molecules and offer substantial advantages compared to conventional small-molecule libraries. Here we developed and streamlined multiple fundamental aspects of DNA-encoded and DNA-templated library synthesis methodology, including computational identification and experimental validation of a 20×20×20×80 set of orthogonal codons, chemical and computational tools for enhancing the structural diversity and drug-likeness of library members, a highly efficient polymerase-mediated template library assembly strategy, and library isolation and purification methods. We integrated these improved methods to produce a second-generation DNA-templated library of 256,000 small-molecule macrocycles with improved drug-like physical properties. In vitro selection of this library for insulin-degrading enzyme (IDE) affinity resulted in novel IDE inhibitors including one of unusual potency and novel macrocycle stereochemistry (IC50 = 40 nM). Collectively, these developments enable DNA-templated small-molecule libraries to serve as more powerful, accessible, streamlined, and cost-effective tools for bioactive small-molecule discovery.

Peptidic inhibitors of insulin-degrading enzyme with potential for dermatological applications discovered via phage display.

Insulin-degrading enzyme (IDE) is an atypical zinc-metalloendopeptidase that hydrolyzes insulin and other intermediate-sized peptide hormones, many of which are implicated in skin health and wound healing. Pharmacological inhibitors of IDE administered internally have been shown to slow the breakdown of insulin and thereby potentiate insulin action. Given the importance of insulin and other IDE substrates for a variety of dermatological processes, pharmacological inhibitors of IDE suitable for topical applications would be expected to hold significant therapeutic and cosmetic potential. Existing IDE inhibitors, however, are prohibitively expensive, difficult to synthesize and of undetermined toxicity. Here we used phage display to discover novel peptidic inhibitors of IDE, which were subsequently characterized in vitro and in cell culture assays. Among several peptide sequences tested, a cyclic dodecapeptide dubbed P12-3A was found to potently inhibit the degradation of insulin (Ki = 2.5 ± 0.31 μM) and other substrates by IDE, while also being resistant to degradation, stable in biological milieu, and highly selective for IDE. In cell culture, P12-3A was shown to potentiate several insulin-induced processes, including the transcription, translation and secretion of alpha-1 type I collagen in primary murine skin fibroblasts, and the migration of keratinocytes in a scratch wound migration assay. By virtue of its potency, stability, specificity for IDE, low cost of synthesis, and demonstrated ability to potentiate insulin-induced processes involved in wound healing and skin health, P12-3A holds significant therapeutic and cosmetic potential for topical applications.

New Medications for the Treatment of Diabetes.

New Medications for the Treatment of Diabetes.

Inhibition of Insulin-Degrading Enzyme Does Not Increase Islet Amyloid Deposition in Vitro.

Islet amyloid deposition in human type 2 diabetes results in β-cell loss. These amyloid deposits contain the unique amyloidogenic peptide human islet amyloid polypeptide (hIAPP), which is also a known substrate of the protease insulin-degrading enzyme (IDE). Whereas IDE inhibition has recently been demonstrated to improve glucose metabolism in mice, inhibiting it has also been shown to increase cell death when synthetic hIAPP is applied exogenously to a β-cell line. Thus, we wanted to determine whether a similar deleterious effect is observed when hIAPP is endogenously produced and secreted from islets. To address this issue, we cultured hIAPP transgenic mouse islets that have the propensity to form amyloid for 48 and 144 hours in 16.7 mM glucose in the presence and absence of the IDE inhibitor 1. At neither time interval did IDE inhibition increase amyloid formation or β-cell loss. Thus, the inhibition of IDE may represent an approach to improve glucose metabolism in human type 2 diabetes, without inducing amyloid deposition and its deleterious effects.

Unraveling Alzheimer's: Making Sense of the Relationship between Diabetes and Alzheimer's Disease1.

Numerous studies have documented a strong association between diabetes and Alzheimer’s disease (AD). The nature of the relationship, however, has remained a puzzle, in part because of seemingly incongruent findings. For example, some studies have concluded that insulin deficiency is primarily at fault, suggesting that intranasal insulin or inhibiting the insulin-degrading enzyme (IDE) could be beneficial. Other research has concluded that hyperinsulinemia is to blame, which implies that intranasal insulin or the inhibition of IDE would exacerbate the disease. Such antithetical conclusions pose a serious obstacle to making progress on treatments. However, careful integration of multiple strands of research, with attention to the methods used in different studies, makes it possible to disentangle the research on AD. This integration suggests that there is an important relationship between insulin, IDE, and AD that yields multiple pathways to AD depending on the where deficiency or excess in the cycle occurs. I review evidence for each of these pathways here. The results suggest that avoiding excess insulin, and supporting robust IDE levels, could be important ways of preventing and lessening the impact of AD. I also describe what further tests need to be conducted to verify the arguments made in the paper, and their implications for treating AD.

Abstract P197: Extracellular Ubiquitin Blocks CXCL12-Induced Proliferation of Cardiac Fibroblasts

CXCR4 receptors mediate in part hypertension-induced cardiac fibrosis. This suggests that endogenous CXCR4-receptor agonists stimulate cardiac fibroblast (CF) proliferation; however, this possibility is unexplored. Although CXCL12 (aka SDF-1α) is the best described endogenous CXCR4 agonist, ubiquitin 1-76 (U-76) exists in the extracellular compartment (10 to 100 nM) and is reported to be a CXCR4 agonist. Therefore, we investigated the ability of both CXCL12 and U-76 to stimulate growth of rat CFs. Low concentrations of CXCL12 (10 nM x 4 days) increased CF proliferation (from 38,973 ± 384 to 44,429 ± 774 cells/well, n=6, p<0.0001), and this effect was augmented by sitagliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor (% increase by CXCL12: without sitagliptin, 14 ± 2 (n=6); with 1 μM of sitagliptin, 38 ± 9, n=6, p<0.0001). This finding is consistent with the known ability of DPP4 to metabolize CXCL12, i.e., sitagliptin inhibits the metabolism of CXCL12 and enhances CXCL12-induced effects. Not only did U-76 at low physiological concentrations (10 nM) not stimulate CF proliferation, U-76 surprisingly nearly abolished CF proliferation induced by CXCL12 + sitagliptin (% increase by CXCL12 + sitagliptin: without U-76, 58 ± 5, n=12; with U-76, 10 ± 7, n=12, p<0.0001). Ubiquitin 1-74 (U-74), a metabolite of U-76, inhibited the pro-growth effects of CXCL12 + sitagliptin 10-fold more potently than did U-76. CFs expressed insulin degrading enzyme (IDE) mRNA (qRT-PCR), protein (western blot), and activity (IDE activity assay) and inhibition of IDE with the newly discovered potent IDE inhibitor 6bK (1 μM) prevented U-76 from blocking the growth effects of CXCL12 + sitagliptin. Analysis by mass spectrometry (selected ion monitoring) demonstrated that CFs converted U-76 to U-74 and this conversion was attenuated by 6bK. Conclusions: CFs express IDE and therefore convert U-76 to U-74; U-74 blocks CXCR4 receptors thus protecting against CXCL12 + DPP4 inhibitor induced CF proliferation. Implications: In patients with low IDE activity (due to genes or drugs) who are treated with DPP4 inhibitors, U-74 (CXCR4 antagonist) levels would be low and CXCL12 (CXCR4 agonist) levels would be high, thus possibly creating a “perfect storm” for CF over-proliferation and cardiac fibrosis.

Structure-activity relationships of imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme.

Insulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-â and insulin. So far the dearth of IDE-specific pharmacological inhibitors impacts the understanding of its role in the physiopathology of Alzheimer's disease, amyloid-â clearance, and its validation as a potential therapeutic target. Hit 1 was previously discovered by high-throughput screening. Here we describe the structure-activity study, that required the synthesis of 48 analogues. We found that while the carboxylic acid, the imidazole and the tertiary amine were critical for activity, the methyl ester was successfully optimized to an amide or a 1,2,4-oxadiazole. Along with improving their activity, compounds were optimized for solubility, lipophilicity and stability in plasma and microsomes. The docking or co-crystallization of some compounds at the exosite or the catalytic site of IDE provided the structural basis for IDE inhibition. The pharmacokinetic properties of best compounds 44 and 46 were measured in vivo. As a result, 44 (BDM43079) and its methyl ester precursor 48 (BDM43124) are useful chemical probes for the exploration of IDE's role.

Insulin-Degrading Enzyme Inhibition, a Novel Therapy for Type 2 Diabetes?

The insulin-degrading enzyme (IDE) has been identified as a type 2 diabetes and Alzheimer's disease susceptibility gene, though its physiological function remains unclear. Maianti etal. (2014) now propose that an IDE inhibitor may be a promising therapeutic strategy for type 2 diabetes.

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 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.

Transcriptional Regulation of Insulin-degrading Enzyme Modulates Mitochondrial Amyloid β (Aβ) Peptide Catabolism and Functionality

Studies of post-mortem brains from Alzheimer disease patients suggest that oxidative damage induced by mitochondrial amyloid β (mitAβ) accumulation is associated with mitochondrial dysfunction. However, the regulation of mitAβ metabolism is unknown. One of the proteases involved in mitAβ catabolism is the long insulin-degrading enzyme (IDE) isoform (IDE-Met(1)). However, the mechanisms of its expression are unknown, and its presence in brain is uncertain. We detected IDE-Met(1) in brain and showed that its expression is regulated by the mitochondrial biogenesis pathway (PGC-1α/NRF-1). A strong positive correlation between PGC-1α or NRF-1 and long IDE isoform transcripts was found in non-demented brains. This correlation was weaker in Alzheimer disease. In vitro inhibition of IDE increased mitAβ and impaired mitochondrial respiration. These changes were restored by inhibition of γ-secretase or promotion of mitochondrial biogenesis. Our results suggest that IDE-Met(1) links the mitochondrial biogenesis pathway with mitAβ levels and organelle functionality.

Optimization of peptide hydroxamate inhibitors of insulin-degrading enzyme reveals marked substrate-selectivity.

Insulin-degrading enzyme (IDE) is an atypical zinc-metallopeptidase that degrades insulin and the amyloid ß-protein and is strongly implicated in the pathogenesis of diabetes and Alzheimer's disease. We recently developed the first effective inhibitors of IDE, peptide hydroxamates that, while highly potent and selective, are relatively large (MW > 740) and difficult to synthesize. We present here a facile synthetic route that yields enantiomerically pure derivatives comparable in potency to the parent compounds. Through the generation of truncated variants, we identified a compound with significantly reduced size (MW = 455.5) that nonetheless retains good potency (ki = 78 ± 11 nM) and selectivity for IDE. Notably, the potency of these inhibitors was found to vary as much as 60-fold in a substrate-specific manner, an unexpected finding for active site-directed inhibitors. Collectively, our findings demonstrate that potent, small-molecule IDE inhibitors can be developed that, in certain instances, can be highly substrate selective.

Geniposide Regulates Insulin-Degrading Enzyme Expression to Inhibit the Cytotoxicity of Aβ1-42 in Cortical Neurons

We reported previously that geniposide showed neurotrophic and neuroprotective activities with the activation of glucagons-like peptide 1 receptor (GLP-1R) in neurons. The current study was designed to further investigate the protective effect of geniposide on β-amyloid (Aβ)-induced cytotoxicity. Our results showed that pre-incubation with geniposide prevented Aβ₁₋₄₂-induced cell injury in primary cultured cortical neurons. Geniposide also induced the expression of insulin-degrading enzyme (IDE), a major degrading protease of Aβ, in a dose-dependent manner. Moreover, bacitracin, an inhibitor of IDE, and RNAi on Glp-1r gene decreased the neuroprotection of geniposide in Aβ₁₋₄₂-treated cortical neurons. Our findings indicated that geniposide activating GLP-1R to against Aβ-induced neurotoxicity involved in its regulation on the expression of IDE in cortical neurons, which provided an additional mechanistic insight into the role of GLP-1R in neuroprotection.

Insulin-degrading Enzyme (IDE): A NOVEL HEAT SHOCK-LIKE PROTEIN

Insulin-degrading enzyme (IDE) is a highly conserved zinc metallopeptidase that is ubiquitously distributed in human tissues, and particularly abundant in the brain, liver, and muscles. IDE activity has been historically associated with insulin and β-amyloid catabolism. However, over the last decade, several experimental findings have established that IDE is also involved in a wide variety of physiopathological processes, including ubiquitin clearance and Varicella Zoster Virus infection. In this study, we demonstrate that normal and malignant cells exposed to different stresses markedly up-regulate IDE in a heat shock protein (HSP)-like fashion. Additionally, we focused our attention on tumor cells and report that (i) IDE is overexpressed in vivo in tumors of the central nervous system (CNS); (ii) IDE-silencing inhibits neuroblastoma (SHSY5Y) cell proliferation and triggers cell death; (iii) IDE inhibition is accompanied by a decrease of the poly-ubiquitinated protein content and co-immunoprecipitates with proteasome and ubiquitin in SHSY5Y cells. In this work, we propose a novel role for IDE as a heat shock protein with implications in cell growth regulation and cancer progression, thus opening up an intriguing hypothesis of IDE as an anticancer target.

Han ethnicity-specific type 2 diabetic treatment from traditional Chinese medicine?

Insulin-degrading enzyme (IDE) gene is one of the type 2 diabetes mellitus susceptibility genes specific to the Han Chinese population. IDE, a zinc-metalloendopeptidase, is a potential target for controlling insulin degradation. Potential lead compounds for IDE inhibition were identified from traditional Chinese medicine (TCM) through virtual screening and evaluation of their pharmacokinetic properties of absorption, distribution, metabolism, excretion, and toxicity. Molecular dynamics (MD) simulation was performed to validate the stability of complexes from docking simulation. The top three TCM compounds, dihydrocaffeic acid, isopraeroside IV, and scopolin, formed stable H–bond interactions with key residue Asn139, and were linked to active pocket residues His108, His112, and Glu189 through zinc. Torsion angle trajectories also indicated some stable interactions for each ligand with IDE. Molecular level analysis revealed that the TCM candidates might affect IDE through competitive binding to the active site and steric hindrance. Structural feature analysis reveals that high amounts of hydroxyl groups and carboxylic moieties contribute to anchor the ligand within the complex. Hence, we suggest the top three TCM compounds as potential inhibitor leads against IDE protein to control insulin degradation for type 2 diabetes mellitus.An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:29

The Components ofFlemingia macrophyllaAttenuate Amyloidβ-Protein Accumulation by Regulating Amyloidβ-Protein Metabolic Pathway

Flemingia macrophylla (Leguminosae) is a popular traditional remedy used in Taiwan as anti-inflammatory, promoting blood circulation and antidiabetes agent. Recent study also suggested its neuroprotective activity against Alzheimer's disease. Therefore, the effects of F. macrophylla on Aβ production and degradation were studied. The effect of F. macrophylla on Aβ metabolism was detected using the cultured mouse neuroblastoma cells N2a transfected with human Swedish mutant APP (swAPP-N2a cells). The effects on Aβ degradation were evaluated on a cell-free system. An ELISA assay was applied to detect the level of Aβ1-40 and Aβ1-42. Western blots assay was employed to measure the levels of soluble amyloid precursor protein and insulin degrading enzyme (IDE). Three fractions of F. macrophylla modified Aβ accumulation by both inhibiting β-secretase and activating IDE. Three flavonoids modified Aβ accumulation by activating IDE. The activated IDE pool by the flavonoids was distinctly regulated by bacitracin (an IDE inhibitor). Furthermore, flavonoid 94-18-13 also modulates Aβ accumulation by enhancing IDE expression. In conclusion, the components of F. macrophylla possess the potential for developing new therapeutic drugs for Alzheimer's disease.

ATP Inhibition of Insulin-Degrading Enzyme: A Computational Study

Alzheimer's Disease (AD) is a neurodegenerative disease associated to abnormal formation and accumulation of tangles of the amyloid-beta (AB) peptide in specific brain regions connected to memory and cognitive functions.[1]Insulin Degrading Enzyme (IDE) is a zinc metalloprotease physiologically regulated by ATP, through a still uncertain mechanism. Its ability to degrade insulin and AB has been investigated for the development of drugs for AD, and understanding this mechanism of activation/inhibition of IDE by ATP can open pathways leading to new therapies.[2]View Large Image | View Hi-Res Image | Download PowerPoint SlideWe show blind docking results, obtained using the program AutoLigand in AutoDockTools, which located seven possible sites of ATP binding in the IDE, from which only three seem likely to influence the mechanism of action of this metalloprotease. We also present Molecular Dynamics and QM/MM simulations aimed at understanding this mechanism of IDE inhibition. Finally, we discuss the action of the enzyme towards degrading AB in the presence or absence of ATP.[1] S. Wang, J. Wu, S. Yamamoto and H.-S. Liu, Biotech. J. 3,165-92 (2008).[2] H. Bernstein, Neuroscience Letters 263, 161-164 (1999).Support: CAPES, FACEPE

Deletion of Insulin-Degrading Enzyme Elicits Antipodal, Age-Dependent Effects on Glucose and Insulin Tolerance

BackgroundInsulin-degrading enzyme (IDE) is widely recognized as the principal protease responsible for the clearance and inactivation of insulin, but its role in glycemic control in vivo is poorly understood. We present here the first longitudinal characterization, to our knowledge, of glucose regulation in mice with pancellular deletion of the IDE gene (IDE-KO mice).MethodologyIDE-KO mice and wild-type (WT) littermates were characterized at 2, 4, and 6 months of age in terms of body weight, basal glucose and insulin levels, and insulin and glucose tolerance. Consistent with a functional role for IDE in insulin clearance, fasting serum insulin levels in IDE-KO mice were found to be ∼3-fold higher than those in wild-type (WT) controls at all ages examined. In agreement with previous observations, 6-mo-old IDE-KO mice exhibited a severe diabetic phenotype characterized by increased body weight and pronounced glucose and insulin intolerance. In marked contrast, 2-mo-old IDE-KO mice exhibited multiple signs of improved glycemic control, including lower fasting glucose levels, lower body mass, and modestly enhanced insulin and glucose tolerance relative to WT controls. Biochemically, the emergence of the diabetic phenotype in IDE-KO mice correlated with age-dependent reductions in insulin receptor (IR) levels in muscle, adipose, and liver tissue. Primary adipocytes harvested from 6-mo-old IDE-KO mice also showed functional impairments in insulin-stimulated glucose uptake.ConclusionsOur results indicate that the diabetic phenotype in IDE-KO mice is not a primary consequence of IDE deficiency, but is instead an emergent compensatory response to chronic hyperinsulinemia resulting from complete deletion of IDE in all tissues throughout life. Significantly, our findings provide new evidence to support the idea that partial and/or transient inhibition of IDE may constitute a valid approach to the treatment of diabetes.

Insulin metabolism in human adipocytes from subcutaneous and visceral depots

Subjects with the metabolic syndrome (insulin resistance, glucose intolerance, dyslipidemia, hypertension, etc.) have a relative increase in abdominal fat tissue compared to normal individuals and obesity has also been shown to be associated with a decrease in insulin clearance. The majority of the clearance of insulin is due to the action of insulin-degrading enzyme (IDE) and IDE is present throughout all tissues. Since abdominal fat is increased in obesity we hypothesized that IDE may be altered in the different fat depots. Adipocytes were isolated from fat samples obtained from subjects during elective abdominal surgery. Fat samples were taken from subcutaneous (SQ) and visceral (VIS) sites. Insulin metabolism was compared in adipocytes isolated from SQ and VIS fat tissue. Adipocytes from the VIS site degraded more insulin that those from SQ fat tissue. Inhibitors of cathepsins B and D has no effect on the degradation of insulin, while bacitracin, an inhibitor of IDE, inhibited degradation by approx. 33% in both SQ and VIS adipocytes. These data show that insulin metabolism is relatively greater in VIS than in SQ fat tissue and potentially due to IDE.

Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin.

BackgroundInsulin is a vital peptide hormone that is a central regulator of glucose homeostasis, and impairments in insulin signaling cause diabetes mellitus. In principle, it should be possible to enhance the activity of insulin by inhibiting its catabolism, which is mediated primarily by insulin-degrading enzyme (IDE), a structurally and evolutionarily distinctive zinc-metalloprotease. Despite interest in pharmacological inhibition of IDE as an attractive anti-diabetic approach dating to the 1950s, potent and selective inhibitors of IDE have not yet emerged.Methodology/Principal FindingsWe used a rational design approach based on analysis of combinatorial peptide mixtures and focused compound libraries to develop novel peptide hydroxamic acid inhibitors of IDE. The resulting compounds are ∼106 times more potent than existing inhibitors, non-toxic, and surprisingly selective for IDE vis-à-vis conventional zinc-metalloproteases. Crystallographic analysis of an IDE-inhibitor complex reveals a novel mode of inhibition based on stabilization of IDE's “closed,” inactive conformation. We show further that pharmacological inhibition of IDE potentiates insulin signaling by a mechanism involving reduced catabolism of internalized insulin.Conclusions/SignificanceThe inhibitors we describe are the first to potently and selectively inhibit IDE or indeed any member of this atypical zinc-metalloprotease superfamily. The distinctive structure of IDE's active site, and the mode of action of our inhibitors, suggests that it may be possible to develop inhibitors that cross-react minimally with conventional zinc-metalloproteases. Significantly, our results reveal that insulin signaling is normally regulated by IDE activity not only extracellularly but also within cells, supporting the longstanding view that IDE inhibitors could hold therapeutic value for the treatment of diabetes.

Size and Stability are Critical Elements in the Substrate Selectivity of Insulin‐Degrading Enzyme

Insulin‐degrading enzyme (IDE) is a zinc metalloprotease involved in the clearance of small bioactive peptides, such as insulin and amyloid‐beta. Given the considerable diversity in substrate tertiary structure, the criteria for substrate recognition and degradation by this protease have been difficult to determine. Here, we evaluate size and local stability as parameters in the substrate selectivity of IDE using opioid peptides and ubiquitin variants as model systems, respectively. Kinetic analyses of IDE, using opioid peptides ranging from 5 to 31 residues, demonstrate that opioid peptides containing 17 or more residues exhibit Km values of 50 μM or less and kcat values that do not exceed 40 s−1. In contrast, smaller opioid peptides exhibited Km values above 900 μM and kcat values above 600 s−1. Mutations at conserved substrate binding sites in IDE are currently being investigated to identify the molecular basis of substrate size discrimination. To probe local stability as a parameter in substrate selectivity, we mutated residues on each of the seven major structural elements of ubiquitin (Ub), a 76‐residue inhibitor of IDE, which destabilize Ub by 0.5–9 kcal/mol. Surprisingly, Ub variants which lose at least 1.6 kcal/mol in local stability are cleaved by IDE with kcat values above 0.5 sec−1. While the first cut site is identical in all digested variants, the cleavage pattern varies with increasing instability of Ub proteins. Together, these findings imply that changing a substrate's property modifies the enzyme's specificity and thus suggest a knowledge basis for the rational design of peptidomimetic modulators of IDE activity.