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@ARTICLE{Malhis:162730,
      author       = {Malhis, Marwa and Kaniyappan, Senthilvelrajan and Aillaud,
                      Isabelle and Chandupatla, Ram Reddy and Ramirez, Lisa-Marie
                      and Zweckstetter, Markus and Horn, Anselm H C and Mandelkow,
                      Eckhard and Sticht, Heinrich and Funke, Susanne Aileen},
      title        = {{P}otent {T}au {A}ggregation {I}nhibitor {D}-{P}eptides
                      {S}elected against {T}au-{R}epeat 2 {U}sing {M}irror {I}mage
                      {P}hage {D}isplay.},
      journal      = {ChemBioChem},
      volume       = {22},
      number       = {21},
      issn         = {1439-7633},
      address      = {Weinheim},
      publisher    = {Wiley-VCH},
      reportid     = {DZNE-2021-01387},
      pages        = {3049 - 3059},
      year         = {2021},
      abstract     = {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 β-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.},
      keywords     = {Humans / Peptide Library / Peptides: chemistry / Peptides:
                      pharmacology / Protein Aggregates: drug effects / tau
                      Proteins: antagonists $\&$ inhibitors / tau Proteins:
                      metabolism / Alzheimer's disease (Other) / D-peptides
                      (Other) / phage display (Other) / tau aggregation inhibitors
                      (Other) / therapy (Other)},
      cin          = {AG (Eva) Mandelkow / AG (Eckhard) Mandelkow / AG
                      Zweckstetter},
      ddc          = {540},
      cid          = {I:(DE-2719)1013015 / I:(DE-2719)1013014 /
                      I:(DE-2719)1410001},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC8596876},
      pubmed       = {pmid:34375027},
      doi          = {10.1002/cbic.202100287},
      url          = {https://pub.dzne.de/record/162730},
}