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@ARTICLE{Ziehm:821057,
      author       = {Ziehm, Tamar and Brener, Oleksandr and van Groen, Thomas
                      and Kadish, Inga and Frenzel, Daniel and Tusche, Markus and
                      Kutzsche, Janine and Reiß, Kerstin and Gremer, Lothar and
                      Nagel-Steger, Luitgard and Willbold, Dieter},
      title        = {{I}ncrease of {P}ositive {N}et {C}harge and
                      {C}onformational {R}igidity {E}nhances the {E}fficacy of d
                      -{E}nantiomeric {P}eptides {D}esigned to {E}liminate
                      {C}ytotoxic {A}β {S}pecies},
      journal      = {ACS chemical neuroscience},
      volume       = {7},
      number       = {8},
      issn         = {1948-7193},
      address      = {Washington, DC},
      publisher    = {ACS Publ.},
      reportid     = {FZJ-2016-06301},
      pages        = {1088 - 1096},
      year         = {2016},
      abstract     = {Alzheimer’s disease (AD) is a neurodegenerative disorder
                      and the most common type of dementia. Until now, there is no
                      curative therapy available. Previously, we selected the
                      amyloid-beta (Aβ) targeting peptide D3 consisting of 12
                      D-enantiomeric amino acid residues by mirror image phage
                      display as a potential drug candidate for the treatment of
                      AD. In the current approach, we investigated the
                      optimization potential of the net charge was investigated
                      and second, cyclization was introduced which is a well-known
                      tool for the optimization of peptides for enhanced target
                      affinity. Following this strategy, three D3 derivatives in
                      addition to D3COOH were designed: C-terminally amidated
                      linear D3 (D3CONH2), cyclic D3 (cD3), and cyclic D3 with an
                      additional arginine residue (cD3r) to maintain the net
                      charge of linear D3CONH2. These four compounds were compared
                      to each other according to their binding affinities to
                      Aβ(1−42), their efficacy to eliminate cytotoxic
                      oligomers, and consequently their potency to neutralize
                      Aβ(1−42) oligomer induced neurotoxicity. D3CONH2 and cD3r
                      versions with equally increased net charge showed superior
                      properties over D3COOH and cD3, respectively. The cyclic
                      versions showed superior properties compared to their linear
                      version with equal net charge, suggesting cD3r to be the
                      most efficient compound among these four. Indeed, treatment
                      of the transgenic AD mouse model Tg-SwDI with cD3r
                      significantly enhanced spatial memory and cognition of these
                      animals as revealed by water maze performance. Therefore,
                      charge increase and cyclization imply suitable modification
                      steps for an optimization approach of the Aβ targeting
                      compound D3.},
      cin          = {ICS-6},
      ddc          = {540},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {553 - Physical Basis of Diseases (POF3-553)},
      pid          = {G:(DE-HGF)POF3-553},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000381717300009},
      pubmed       = {pmid:27240424},
      doi          = {10.1021/acschemneuro.6b00047},
      url          = {https://juser.fz-juelich.de/record/821057},
}