Abstract
Amylin or hIAPP, together with insulin, plays a significant role in glucose metabolism. However, it undergoes β-sheet rich amyloid formation associated with pancreatic β-cell dysfunction leading to type-2 diabetes (T2D). Recent studies suggest that restricting β-sheet formation in it may halt amyloid formation, which may limit the risk for the disease. Several peptide-based inhibitors have been reported to prevent aggregation. However, most of them have limitations, including low binding efficiency, active only at higher doses, poor solubility, and proteolytic degradation. Insertion of non-coded amino acids renders proteolytically stable peptides. We incorporated a structurally rigid β-amino acid, Anthranilic acid (Ant), at different sites within the central hydrophobic region of hIAPP and developed two singly mutated hIAPP8–37 peptidomimetics. These peptidomimetics inhibited the amyloid formation of hIAPP substantially even at low concentration, as evident from in vitro ThT, CD, FT-IR, TEM, and Congo red staining birefringence results. These peptidomimetics also disrupted the preformed aggregates formed by hIAPP into non-toxic species. These β-amino acid-based peptidomimetics can be an attractive scaffold for therapeutic design towards T2D or other protein misfolding diseases.
Highlights
Protein misfolding and amyloid aggregation cause many human diseases, including Alzheimer’s disease (AD), Type II Diabetes (T2D), and Parkinson’s disease.[1]
Amylin or human Islet Amyloid Polypeptide (hIAPP), together with insulin, plays a significant role in glucose metabolism. It undergoes b-sheet rich amyloid formation associated with pancreatic b-cell dysfunction leading to type-2 diabetes (T2D)
We previously demonstrated the inhibitory efficacy of b-sheet breaker hybrid peptidomimetics (BSBHPs) by inserting one breaker element, isomers of aminobenzoic acid, into the core hydrophobic region of hIAPP
Summary
Protein misfolding and amyloid aggregation cause many human diseases, including Alzheimer’s disease (AD), Type II Diabetes (T2D), and Parkinson’s disease.[1] Despite the morphological variations, amyloid aggregates causing these diseases are rich in highly ordered cross-b-sheet structures.[2] Amylin or human Islet Amyloid Polypeptide (hIAPP), co-secreted with insulin from pancreatic b-cell, changes from non-toxic monomers to toxic oligomers at physiological conditions These toxic oligomers form pores in the b-cell membrane causing b-cell death. The Ant containing small BSBHPs was found useful to inhibit the aggregation of hIAPP and disrupt its preformed fibrillar assemblies at a relatively higher dose (10-fold molar excess) These BSHBPs are stable towards proteolytic degradation due to non-coded b-amino acid Ant.[12] these BSBHPs may not effectively bind with the full-length hIAPP due to smaller size and lack of residual interaction. The mechanism is not fully understood, it is hypothesized that the inhibitors need to bind with the growing fibrils of the aggregating peptide to inhibit aggregation, and a mutant of the full-length hIAPP may bind more tightly than the small fragment of hIAPP.[7,19] we decided to synthesize a new set of peptidomimetics, comprising of hIAPP8–37 with a single point mutation at different positions, which are expected to exhibit inhibitory effect at fewer molar ratios compared to the smaller hIAPP22–27 variant (Scheme 1)
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