Fig. 1: ACM design concept, their effects on IAPP amyloid self-assembly and cytotoxicity, and ACM secondary structures. | Nature Communications

Fig. 1: ACM design concept, their effects on IAPP amyloid self-assembly and cytotoxicity, and ACM secondary structures.

From: Designed peptides as nanomolar cross-amyloid inhibitors acting via supramolecular nanofiber co-assembly

Fig. 1: ACM design concept, their effects on IAPP amyloid self-assembly and cytotoxicity, and ACM secondary structures.The alternative text for this image may have been generated using AI.

a Sequences of IAPP and Aβ40(42), proposed models of fIAPP and fAβ40 folds, and hypothetical IAPP/Aβ40 “hetero-amyloids” (β-strands, pink or blue and underlined; “hot segments” of self-/cross-interactions, bold; loop residues, italics)25,30,31. b ACM inhibitor design strategy. Template Aβ(15–40) in a β-strand-loop-β-strand fold proposed for fAβ4031 is modified via (a) N-methylations in Aβ(17–20), b substitution of Aβ(24-26) by hydrophobic tripeptides, and c Met35 substitution by Nle. c Sequences of the six ACMs and negative controls VGS-VF and VGS-LF (Supplementary Table 1). Each sequence corresponds to two different ACMs which contain the same LTS but a different couple of N-methylated residues (dashed boxes). Color code as in a; LTS and tripeptide VGS in red; green or violet for peptide names and corresponding N-methylated residues. d Nle3-VF, L3-VF, and F3-VF block IAPP amyloid self-assembly. Fibrillogenesis of IAPP (16.5 µM) alone or with ACMs or VGS-VF was assessed via ThT binding (IAPP/peptide 1/2) (means ± SD, n = 3 independent assays). e Nle3-VF, L3-VF, and F3-VF suppress the formation of toxic IAPP assemblies. Solutions of d (7-day-aged (VFS-VF 24 h)) added to RIN5fm cells; cell viability determined via MTT reduction (means ± SD, three independent assays, n = 3 technical replicates each). f Nle3-LF, L3-LF, and F3-LF block IAPP amyloid self-assembly. Assay as in d (IAPP/peptide 1/2 except L3-LF (1/2.5)) (means ± SD, three independent assays). g Nle3-LF, L3-LF, and F3-LF suppress the formation of toxic IAPP assemblies. Solutions of f (7-day-aged (VGS-LF 24 h)) added to RIN5fm cells; cell viability determined via MTT reduction (means ± SD, three independent assays, n = 3 technical replicates each). h, i Secondary structure of ACMs. Far-UV CD spectra of ACMs of d and f versus non-inhibitors (5 µM, pH 7.4). j ACMs inhibit seeding of IAPP by preformed fIAPP. Fibrillogenesis of IAPP (12 µM) without or with fIAPP seeds (10%) and seeded IAPP/ACM mixtures assessed via ThT binding (IAPP/ACM 1/2) (means ± SD, n = 9 (for IAPP alone) or 3 (for all other samples) independent assays). k ACMs inhibit fAβ42-mediated cross-seeding of IAPP. Fibrillogenesis of IAPP with and without fAβ42 seeds (10%) versus IAPP/ACM mixtures (IAPP 12 µM, IAPP/ACM 1/2) (means ± SD, n = 6 (for IAPP with or without seeds) or n = 3 (for all other samples) independent assays).

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