Jun 17, 2018

Designed Macrocyclic Peptides as Nanomolar Amyloid Inhibitors Based on Minimal Recognition Elements

Angewandte Chemie
Anna SpanopoulouAphrodite Kapurniotu

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 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.

Mentioned in this Paper

Human plasma
Diabetes Mellitus, Non-Insulin-Dependent
Amyloidogenesis
Pathogenic Aspects
MCIP-1 protein, rat
Blood - Brain Barrier Anatomy
Pathogenesis
Clinic
APP protein, human
Amyloid beta-protein precursor inhibitor

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