2018
DOI: 10.1002/anie.201802979
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Designed Macrocyclic Peptides as Nanomolar Amyloid Inhibitors Based on Minimal Recognition Elements

Abstract: Amyloid self-assembly is linked to the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes (T2D), but so far, no anti-amyloid compound has reached the clinic. Macrocyclic peptides belong to the most attractive drug candidates. Herein we present macrocyclic peptides (MCIPs) designed using minimal IAPP-derived recognition elements as a novel class of nanomolar amyloid inhibitors of both Aβ40(42) and IAPP or Aβ40(42) alone and show that chirality controls inhibitor selectivity. Sequence optimization led … Show more

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Cited by 39 publications
(46 citation statements)
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References 26 publications
(83 reference statements)
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“…b) Design concept, inhibitory effects, and suggested mechanism of the inhibitor function of ISMs . c) Minimalistic design concept, sequences, and functions of the MCIPs …”
Section: Peptide‐based Molecular Strategies To Inhibit Amyloid Formationmentioning
confidence: 99%
“…b) Design concept, inhibitory effects, and suggested mechanism of the inhibitor function of ISMs . c) Minimalistic design concept, sequences, and functions of the MCIPs …”
Section: Peptide‐based Molecular Strategies To Inhibit Amyloid Formationmentioning
confidence: 99%
“…Thecorrect spatial arrangement of side chains allows them to efficiently capture Ab40 and direct it into off-pathway non-toxic aggregates. [24] Figure 7s chematically illustrates different amyloid selfassembly inhibition mechanisms involving classical single-site binding,t ogether with intervention strategies that employ colloid formation or the here suggested ISM-induced LLPSlike process.S ingle-site binding events are the classical paradigm for ad rug-enzyme complex. Because of the low affinity and the lack of deep binding pockets,t his class of inhibitors is not very effective for amyloids (Figure 7, top).…”
Section: Discussionmentioning
confidence: 99%
“…Thedesign of the ISMs was based on the finding that amyloids are generally composed of a b-sheet-turn-b-sheet structural motif and that IAPP uses the same two binding regions for both its amyloid self-and its cross-amyloid hetero-assembly with Ab40/42. [1a, 2] ISMs were thus derived by linking the two hot segments IAPP (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) and IAPP (22)(23)(24)(25)(26)(27)(28) in native or N-methylated form to each other via different linkers,mostly tripeptide sequences consisting of identical amino acids;notably,these two segments are highly homologous to segments of the amyloid core of Ab. [3] High Ab40/42 anti-amyloidogenic activity was found for seven out of the 16 studied ISMs with six of them containing bulky hydrophobic/aromatic residues (e.g.L LL, III, FFF) in the linker tripeptide and one of them, termed R3-GI, the RRR tripeptide.…”
Section: Introductionmentioning
confidence: 99%
“…[41] Diese so genannten "Macrocyclic Inhibitory Peptides" (MCIPs) ahmen funktionelle (inhibitorische) IAPP-Interaktionsflächen nach, während sie zugleich minimale IAPP-basierte Erkennungselemente beibehalten (Abbildung 7 c). [41,47] [6,49] Auf der Suche nach Strategien zur Reduktion der nicht-nativen Aggregation von Insulin, die zu Komplikationen bei seiner biomedizinischen Anwendbarkeit führt, identifizierten wir IAPP-GI als einen nanomolaren Inhibitor. [11d] Erwartungsgemäß interferiert die IAPP-GI-Insulin-Wechselwirkung nicht mit der Insulinfunktion, da IAPP-GI ein Analog des nativ vorkommenden Insulin-Interaktionspartners IAPP ist.…”
Section: Inhibitordesign Auf Basis Der Iapp-ab-kreuzwechselwirkungunclassified