Charge-Based Inhibitors of Amylin Fibrillization and Toxicity

Figure 1

Design of fibrillization inhibitors. (a) Sequences of WT amylin and the three peptide analogs that incorporate strings of positive or negative charges in the amylin sequence. (b) Model of the stacked -hairpin structure of amylin fibrils based on ssNMR [13]. Positively charged arginine residues are shown as spheres that are positioned at the end of strand 1 in Arg-1 (blue) or at the start of strand 2 in Arg-2 (green). (c) Solution NMR model of micelle-bound amylin, in which the N-terminal residues 5–17 are embedded in the hydrophobic environment of the micelle [16]. The Mem-T peptide substitutes hydrophobic residues in this region for five aspartates (red), in order to interfere with membrane binding through electrostatic repulsion between negatively charged residues on the peptide and lipid head-groups.

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