Exploiting Cross-Amyloid Interactions To Inhibit Protein Aggregation but not Function: Nanomolar Affinity Inhibition of Insulin Aggregation by an IAPP Mimic

Laboratory of Peptide Biochemistry, Center for Integrated Protein Science München, Technische Universität München, An der Saatzucht 5, 85350 Freising-Weihenstephan, Germany.
Angewandte Chemie International Edition (Impact Factor: 11.26). 09/2008; 47(37):7114-8. DOI: 10.1002/anie.200801499
Source: PubMed


Potential aggregate preventer: The designed peptide IAPP-GI inhibits the non-native aggregation of insulin without affecting its function. As the peptide also blocks aggregation of key amyloid peptides that occur in Alzheimer's disease and type II diabetes, it is a promising drug candidate.

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    • "It was shown that the so-called IAPP-GI peptide efficiently inhibits IAPP amyloid formation and cytotoxicity [13], [17]. More interestingly, IAPP-GI was demonstrated to block cytotoxic assembly of Aβ and insulin as well [18], [19]. The cross-association reaction between IAPP-GI (or nonfibrillar IAPP conformers) and Aβ may have some implications beyond its therapeutic potentials, and along with clinical and epidemiological evidences, provide a potential molecular link between AD and adult-onset diabetes [20]. "
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    ABSTRACT: Assembly of amyloid-beta peptide (Aβ) into cytotoxic oligomeric and fibrillar aggregates is believed to be a major pathologic event in Alzheimer's disease (AD) and interfering with Aβ aggregation is an important strategy in the development of novel therapeutic approaches. Prior studies have shown that the double N-methylated analogue of islet amyloid polypeptide (IAPP) IAPP-GI, which is a conformationally constrained IAPP analogue mimicking a non-amyloidogenic IAPP conformation, is capable of blocking cytotoxic self-assembly of Aβ. Here we investigate the interaction of IAPP-GI with Aβ40 and Aβ42 using NMR spectroscopy. The most pronounced NMR chemical shift changes were observed for residues 13-20, while residues 7-9, 15-16 as well as the C-terminal half of Aβ--that is both regions of the Aβ sequence that are converted into β-strands in amyloid fibrils--were less accessible to solvent in the presence of IAPP-GI. At the same time, interaction of IAPP-GI with Aβ resulted in a concentration-dependent co-aggregation of Aβ and IAPP-GI that was enhanced for the more aggregation prone Aβ42 peptide. On the basis of the reduced toxicity of the Aβ peptide in the presence of IAPP-GI, our data are consistent with the suggestion that IAPP-GI redirects Aβ into nontoxic "off-pathway" aggregates.
    Full-text · Article · May 2011 · PLoS ONE
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    ABSTRACT: The islet amyloid polypeptide (IAPP) or amylin is a pancreatic hormone and crucially involved in the pathogenesis of type-II diabetes mellitus (T2DM). Aggregation and amyloid formation of IAPP is considered as the primary culprit for pancreatic beta-cell loss in T2DM patients. In this study, first X-ray reflectivity (XRR) measurements on IAPP at lipid interfaces have been carried out, providing a molecular level characterization of the first steps of the lipid-induced fibrillation process of IAPP, which is initiated by lipid-induced nucleation, oligomerization, followed by detachment of larger IAPP aggregate structures from the lipid membrane, and terminated by the formation of mature fibrils in the bulk solution. The adsorption process of IAPP at lipid interfaces in the absence and presence of negatively charged lipid has also been studied by complementary ATR-FTIR spectroscopic measurements. The morphological properties were followed by atomic force microscopy (AFM). Moreover, we show that the polyphenolic red wine compound resveratrol is able to inhibit IAPP aggregation also in the presence of aggregation-fostering negatively charged lipid interfaces, revealing its potential as a drug candidate for T2DM.
    No preview · Article · Aug 2009 · Journal of the American Chemical Society
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    ABSTRACT: Amyloid fibril formation is a common event in more than twenty human diseases and in some normal physiological processes. The mechanism of this ordered aggregation process and the molecular forces driving it are therefore of great importance. One of the strategies used in this field is targeting the fibrillization process by different factors, like, short peptides, organic molecules, etc. Here, we targeted insulin fibril formation by a range of small aromatic molecules, with different numbers of aromatic rings and various substituent groups. Using Thioflavin T fluorescence assay and transmission electron microscopy, we found that all dicyclic and tricyclic compounds in our screen were efficient inhibitors of insulin fibril formation. A common notion regarding amyloid inhibitors is that two functional groups are essentials for interfering with the amyloid formation process; a recognition motif and a bulky group for inducing a steric interference. However, here, we showed that some monocyclic compounds as small as toluene were also found to inhibit fibrillization. In addition, we found that substituent of benzene ring have a great influence on the inhibitory potency. Specifically, cyano, methyl and nitro groups increased the inhibitory potency. The results introduced here may contribute to future rational design of amyloid inhibitors.
    No preview · Article · Nov 2009 · Islets
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