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@ARTICLE{Bochicchio:829374,
      author       = {Bochicchio, Anna and Jordaan, Sandra and Losasso, Valeria
                      and Chetty, Shivan and Casasnovas Perera, Rodrigo and
                      Ippoliti, Emiliano and Barth, Stefan and Carloni, Paolo},
      title        = {{D}esigning the {S}niper: {I}mproving {T}argeted {H}uman
                      {C}ytolytic {F}usion {P}roteins for {A}nti-{C}ancer
                      {T}herapy via {M}olecular {S}imulation},
      journal      = {Biomedicines},
      volume       = {5},
      number       = {1},
      issn         = {2227-9059},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {FZJ-2017-03087},
      pages        = {9},
      year         = {2017},
      abstract     = {Targeted human cytolytic fusion proteins (hCFPs) are
                      humanized immunotoxins for selective treatment of different
                      diseases including cancer. They are composed of a ligand
                      specifically binding to target cells genetically linked to a
                      human apoptosis-inducing enzyme. hCFPs target cancer cells
                      via an antibody or derivative (scFv) specifically binding to
                      e.g., tumor associated antigens (TAAs). After
                      internalization and translocation of the enzyme from
                      endocytosed endosomes, the human enzymes introduced into the
                      cytosol are efficiently inducing apoptosis. Under in vivo
                      conditions such enzymes are subject to tight regulation by
                      native inhibitors in order to prevent inappropriate
                      induction of cell death in healthy cells. Tumor cells are
                      known to upregulate these inhibitors as a survival mechanism
                      resulting in escape of malignant cells from elimination by
                      immune effector cells. Cytosolic inhibitors of Granzyme B
                      and Angiogenin (Serpin P9 and RNH1, respectively), reduce
                      the efficacy of hCFPs with these enzymes as effector
                      domains, requiring detrimentally high doses in order to
                      saturate inhibitor binding and rescue cytolytic activity.
                      Variants of Granzyme B and Angiogenin might feature reduced
                      affinity for their respective inhibitors, while retaining or
                      even enhancing their catalytic activity. A powerful tool to
                      design hCFPs mutants with improved potency is given by in
                      silico methods. These include molecular dynamics (MD)
                      simulations and enhanced sampling methods (ESM). MD and ESM
                      allow predicting the enzyme-protein inhibitor binding
                      stability and the associated conformational changes,
                      provided that structural information is available. Such
                      “high-resolution” detailed description enables the
                      elucidation of interaction domains and the identification of
                      sites where particular point mutations may modify those
                      interactions. This review discusses recent advances in the
                      use of MD and ESM for hCFP development from the viewpoints
                      of scientists involved in both fields.},
      cin          = {IAS-5 / INM-9},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {899 - ohne Topic (POF3-899)},
      pid          = {G:(DE-HGF)POF3-899},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000398714600009},
      pubmed       = {pmid:28536352},
      doi          = {10.3390/biomedicines5010009},
      url          = {https://juser.fz-juelich.de/record/829374},
}