期刊
CHEMBIOCHEM
卷 22, 期 21, 页码 3049-3059出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202100287
关键词
Alzheimer's disease; D-peptides; phage display; tau aggregation inhibitors; therapy
资金
- grant of TechnologieAllianzOberfranken (TAO)
- Landeskonferenz der Frauenbeauftragten, Bavaria, Germany
- Katharina Hardt Foundation
- Alzheimer Forschung Initiative e.V. (AFI)
- European Research Council (ERC) under the EU Horizon 2020 research and innovation programme [787679]
- Projekt DEAL
The study identified D-enantiomeric peptides MMD3 and its retro-inverso form, MMD3rev, as inhibitors of fibrillization of the PHF6* peptide, the repeat domain of Tau and full-length Tau in in vitro studies. The peptides prevented the formation of beta-sheet-rich fibrils by diverting Tau into large amorphous aggregates, suggesting their potential as therapeutic and diagnostic molecules in Alzheimer's disease research.
Alzheimer's disease and other Tauopathies are associated with neurofibrillary tangles composed of Tau protein, as well as toxic Tau oligomers. Therefore, inhibitors of pathological Tau aggregation are potentially useful candidates for future therapies targeting Tauopathies. Two hexapeptides within Tau, designated PHF6* (275-VQIINK-280) and PHF6 (306-VQIVYK-311), are known to promote Tau aggregation. Recently, the PHF6* segment has been described as the more potent driver of Tau aggregation. We therefore employed mirror-image phage display with a large peptide library to identify PHF6* fibril binding peptides consisting of D-enantiomeric amino acids. The suitability of D-enantiomeric peptides for in vivo applications, which are protease stable and less immunogenic than L-peptides, has already been demonstrated. The identified D-enantiomeric peptide MMD3 and its retro-inverso form, designated MMD3rev, inhibited in vitro fibrillization of the PHF6* peptide, the repeat domain of Tau as well as full-length Tau. Dynamic light scattering, pelleting assays and atomic force microscopy demonstrated that MMD3 prevents the formation of tau beta-sheet-rich fibrils by diverting Tau into large amorphous aggregates. NMR data suggest that the D-enantiomeric peptides bound to Tau monomers with rather low affinity, but ELISA (enzyme-linked immunosorbent assay) data demonstrated binding to PHF6* and full length Tau fibrils. In addition, molecular insight into the binding mode of MMD3 to PHF6* fibrils were gained by in silico modelling. The identified PHF6*-targeting peptides were able to penetrate cells. The study establishes PHF6* fibril binding peptides consisting of D-enantiomeric amino acids as potential molecules for therapeutic and diagnostic applications in AD research.
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