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 to the discovery of an Aβ40(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.

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 to the discovery of an Aβ40(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.

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