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Spanopoulou, Anna; Heidrich, Luzia; Chen, Hong-Ru; Frost, Christina; Hrle, Dean; Malideli, Eleni; Hille, Kathleen; Grammatikopoulos, Alexandros; Bernhagen, Jürgen; Zacharias, Martin; Rammes, Gerhard; Kapurniotu, Aphrodite (2018): Designed Macrocyclic Peptides as Nanomolar Amyloid Inhibitors Based on Minimal Recognition Elements. In: Angewandte Chemie-International Edition, Vol. 57, No. 44: pp. 14503-14508
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Amyloid self-assembly is linked to the pathogenesis of Alzheimer's disease (AD) and type2 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 A40(42) and IAPP or A40(42) alone and show that chirality controls inhibitor selectivity. Sequence optimization led to the discovery of an A40(42)-selective MCIP exhibiting high proteolytic stability in human plasma and human blood-brain barrier (BBB) crossing ability in a cell model, two highly desirable properties for anti-amyloid AD drugs. Owing to their favorable properties, MCIPs should serve as leads for macrocyclic peptide-based anti-amyloid drugs and scaffolds for the design of small-molecule peptidomimetics for targeting amyloidogenesis in AD or in both AD and T2D.