A hIAPP‐derived all‐d‐amino‐acid inhibits hIAPP fibrillation efficiently at membrane surface by targeting α‐helical oligomeric intermediates

Abstract

Edited by Sandro Sonnino ) is demonstrated to inhibit hIAPP fibril formation efficiently both at the phospholipid membrane and in bulk solution. The inhibitor terminates hIAPP aggregation to the a-helical oligomeric intermediates at the membrane surface, whereas it stops the aggregation at the stage of b-sheet oligomeric intermediates in bulk solution. This is the first evidence that the inhibition mechanism of the inhibitor at membrane surface is significantly different from that in bulk solution. Structured summary of protein interactions:hIAPP and hIAPP bind by transmission electron microscopy (View interaction) hIAPP and hIAPP bind by atomic force microscopy (View interaction) hIAPP and hIAPP bind by fluorescence technology (View interaction) hIAPP and hIAPP bind by dynamic light scattering (View interaction)

A new strategy to reconcile amyloid cross‐seeding and amyloid prevention in a binary system of α‐synuclein fragmental peptide and hIAPP

“…7,8 Particularly, numerous research works have developed different types of amyloid inhibitors against hIAPP aggregation, including small molecules, [9][10][11][12][13] polymers, 14,15 nanoparticles, 16,17 and peptides. 18,19 These amyloid hIAPP inhibitors achieve their inhibition functions via different ways 8,20 by (a) delaying or preventing the misfolding of hIAPP into β-strand structures, (b) remodeling hIAPP aggregation pathways away from key neurotoxic species, (c) forming less toxic or nontoxic hIAPPinhibitor complexes, (d) disintegrating toxic species, and (e) attenuating the hIAPP-induced cell toxicity. Almost all of these inhibitors are effective to inhibit hIAPP aggregation, but none of them have achieved to clinical success for T2D treatment.…”

Mechanism of Inhibition of Human Islet Amyloid Polypeptide-Induced Membrane Damage by a Small Organic Fluorogen

“…Different types of inhibitors have been reported, including short peptides derived from the hIAPP sequence 14 15 16 , native proteins and their fragments 17 18 19 20 21 22 , and organic compounds 11 12 13 . These inhibitors were mainly tested for their effects in inhibiting hIAPP fibrillization, and few works have been conducted to determine their effects in protecting membranes from lysing by hIAPP 11 13 16 . Based on the mechanisms revealed in this work, we propose that a potent inhibitor that can prevent a membrane from being damaged by hIAPP should have capabilities to either screen the hydrophobic portion of hIAPP, neutralize the charges of hIAPP, or both.…”

“…Several mechanisms of IAPP-induced cytotoxicity have been proposed; for example, in one mechanism, membrane pores are initially induced by intermediate-sized peptide aggregates 3 4 5 6 7 ; in another mechanism membrane damage occurs during the growth of IAPP fibrils 8 9 10 . Therefore, quite abundant inhibitors, including organic molecules 11 12 13 , fragments of hIAPP 14 15 16 , and variant native proteins and their fragments 17 18 19 20 21 22 have been tested by characterizing their activities and the mechanism of inhibition of fibril formation or cytotoxicity.…”

“…They found that aromatic residues were not required for membrane damage, but the membrane damage was sensitive to the protonation state of histidine in the helical region. Based on the hypothesis that the membrane-bound α -helical IAPP oligomers represented the toxic species and are on pathway to amyloid formation, various amyloid inhibitors have been screened to identify their ability of inhibition 12 13 14 15 16 17 18 19 20 21 22 , especially the ability to bind with the α -helical states of hIAPP 11 .…”

Investigation on the effect of three isoflavones on the fibrillation of hen egg‐white lysozyme

“…At present, most therapeutic approaches are mainly based on prevention of amyloid fibril formation and clearance of amyloid aggregate include stabilizing the natural structure of proteins, direct inhibiting the production of amyloidogenic forms, clearing amyloid aggregates, and redirecting amyloid fibril formation into non‐cytotoxic pathways 4,5 . To this end, many reagents, including several metal ions, 2,6 nanomaterials, 7,8 and peptides, 9 have been evaluated their effect on prevention of protein aggregation. However, because of weak targeting, poor permeability, and cytotoxicity, many of these reagents are not ideal inhibitors of protein fibrillation.…”