A Hot-Segment-Based Approach for the Design of Cross-Amyloid Interaction Surface Mimics as Inhibitors of Amyloid Self-Assembly.
The design of inhibitors of protein-protein interactions mediating amyloid self-assembly is a major challenge mainly due to the dynamic nature of the involved structures and interfaces. Interactions of amyloidogenic polypeptides with other proteins are important modulators of self-assembly. Here we present a hot-segment-linking approach to design a series of mimics of the IAPP cross-amyloid interaction surface with Aβ (ISMs) as nanomolar inhibitors of amyloidogenesis and cytotoxicity of Aβ, IAPP, or both polypeptides. The nature of the linker determines ISM structure and inhibitory function including both potency and target selectivity. Importantly, ISMs effectively suppress both self- and cross-seeded IAPP self-assembly. Our results provide a novel class of highly potent peptide leads for targeting protein aggregation in Alzheimer's disease, type 2 diabetes, or both diseases and a chemical approach to inhibit amyloid self-assembly and pathogenic interactions of other proteins as well.
Division of Peptide Biochemistry, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354 Freising (Germany).
Erika
E
Andreetto
Division of Peptide Biochemistry, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354 Freising (Germany).
Eleni
E
Malideli
Division of Peptide Biochemistry, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354 Freising (Germany).
Li-Mei
LM
Yan
Division of Peptide Biochemistry, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354 Freising (Germany).
Michael
M
Kracklauer
Division of Peptide Biochemistry, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354 Freising (Germany).
Karine
K
Farbiarz
Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen (Germany).
Marianna
M
Tatarek-Nossol
Department of Anesthesiology, Technische Universität München/Klinikum Rechts der Isar, München (Germany).
Gerhard
G
Rammes
Department of Chemistry, Technische Universität München, Garching (Germany).|Helmholtz Zentrum Muenchen (HMGU), Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg (Germany).
Elke
E
Prade
Department of Anesthesiology, Technische Universität München/Klinikum Rechts der Isar, München (Germany).
Tatjana
T
Neumüller
Division of Peptide Biochemistry, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354 Freising (Germany).
Andrea
A
Caporale
Division of Peptide Biochemistry, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354 Freising (Germany).
Anna
A
Spanopoulou
Division of Peptide Biochemistry, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354 Freising (Germany).
Maria
M
Bakou
Department of Chemistry, Technische Universität München, Garching (Germany).|Helmholtz Zentrum Muenchen (HMGU), Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg (Germany).
Bernd
B
Reif
Division of Peptide Biochemistry, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354 Freising (Germany). akapurniotu@wzw.tum.de.
Aphrodite
A
Kapurniotu
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects; D013499:Surface Properties
D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide; D066329:Protein Aggregates
Alzheimer’s disease; amyloid inhibitors; islet amyloid polypeptide; protein-protein interactions; β-amyloid peptide