Optimization of d-Peptides for Aβ Monomer Binding Specificity Enhances Their Potential to Eliminate Toxic Aβ Oligomers

Antonia Nicole Klein; Tamar Ziehm; Thomas van Groen; Inga Kadish; Anne Elfgen; Markus Tusche; Maren Thomaier; Kerstin Reiss; Oleksandr Brener; Lothar Gremer; Janine Kutzsche; Dieter Willbold

doi:10.1021/acschemneuro.7b00045

Optimization of d-Peptides for Aβ Monomer Binding Specificity Enhances Their Potential to Eliminate Toxic Aβ Oligomers

ACS Chem Neurosci. 2017 Sep 20;8(9):1889-1900. doi: 10.1021/acschemneuro.7b00045. Epub 2017 Jun 23.

Authors

Antonia Nicole Klein¹, Tamar Ziehm¹, Thomas van Groen², Inga Kadish², Anne Elfgen¹, Markus Tusche¹, Maren Thomaier¹, Kerstin Reiss¹, Oleksandr Brener^{1

3}, Lothar Gremer^{1

3}, Janine Kutzsche¹, Dieter Willbold^{1

3}

Affiliations

¹ Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich , 52425 Jülich, Germany.
² Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham , Birmingham, Alabama 35294, United States.
³ Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf , 40225 Düsseldorf, Germany.

PMID: 28581708
DOI: 10.1021/acschemneuro.7b00045

Abstract

Amyloid-beta (Aβ) oligomers are thought to be causative for the development and progression of Alzheimer's disease (AD). Starting from the Aβ oligomer eliminating d-enantiomeric peptide D3, we developed and applied a two-step procedure based on peptide microarrays to identify D3 derivatives with increased binding affinity and specificity for monomeric Aβ(1-42) to further enhance the Aβ oligomer elimination efficacy. Out of more than 1000 D3 derivatives, we selected seven novel d-peptides, named ANK1 to ANK7, and characterized them in more detail in vitro. All ANK peptides bound to monomeric Aβ(1-42), eliminated Aβ(1-42) oligomers, inhibited Aβ(1-42) fibril formation, and reduced Aβ(1-42)-induced cytotoxicity more efficiently than D3. Additionally, ANK6 completely inhibited the prion-like propagation of preformed Aβ(1-42) seeds and showed a nonsignificant tendency for improving memory performance of tg-APPSwDI mice after i.p. application for 4 weeks. This supports the hypothesis that stabilization of Aβ monomers and thereby induced elimination of Aβ oligomers is a suitable therapeutic strategy.

Keywords: Alzheimer’s disease; amyloid-beta; d-peptides; drug development; optimization; peptide microarrays.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / drug therapy
Alzheimer Disease / metabolism
Alzheimer Disease / pathology
Alzheimer Disease / psychology
Amyloid beta-Peptides / antagonists & inhibitors*
Amyloid beta-Peptides / metabolism*
Amyloid beta-Peptides / toxicity
Amyloid beta-Peptides / ultrastructure
Amyloid beta-Protein Precursor / genetics
Amyloid beta-Protein Precursor / metabolism
Animals
Animals, Genetically Modified
Binding, Competitive
Cell Line, Tumor
Cell Survival / drug effects
Cell Survival / physiology
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Discovery
Female
Humans
Mice, Inbred C57BL
Microarray Analysis
Neuroprotective Agents / pharmacology*
Nootropic Agents / pharmacology*
Oligopeptides / pharmacology*
Peptide Fragments / antagonists & inhibitors*
Peptide Fragments / metabolism*
Peptide Fragments / toxicity
Peptide Fragments / ultrastructure
Plaque, Amyloid / drug therapy
Plaque, Amyloid / metabolism
Plaque, Amyloid / pathology
Presenilin-1 / genetics
Presenilin-1 / metabolism
Protein Aggregation, Pathological / drug therapy
Protein Aggregation, Pathological / metabolism
Protein Aggregation, Pathological / pathology
Recombinant Proteins / metabolism
Recombinant Proteins / toxicity
Recombinant Proteins / ultrastructure

Substances

APP protein, human
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Neuroprotective Agents
Nootropic Agents
Oligopeptides
PSEN1 protein, human
Peptide Fragments
Presenilin-1
Recombinant Proteins
amyloid beta-protein (1-42)