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@ARTICLE{Sevenich:906319,
      author       = {Sevenich, Marc and Thul, Elena and Lakomek, Nils-Alexander
                      and Klünemann, Thomas and Schubert, Maren and Bertoglio,
                      Federico and van den Heuvel, Joop and Petzsch, Patrick and
                      Mohrlüder, Jeannine and Willbold, Dieter},
      title        = {{P}hage {D}isplay-{D}erived {C}ompounds {D}isplace h{ACE}2
                      from {I}ts {C}omplex with {SARS}-{C}o{V}-2 {S}pike
                      {P}rotein},
      journal      = {Biomedicines},
      volume       = {10},
      number       = {2},
      issn         = {2227-9059},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {FZJ-2022-01369},
      pages        = {441 -},
      year         = {2022},
      abstract     = {Severe respiratory syndrome coronavirus-2 (SARS-CoV-2) is a
                      highly contagious beta-class coronavirus. Although
                      vaccinations have shown high efficacy, the emergence of
                      novel variants of concern (VOCs) has already exhibited
                      traits of immune evasion. Thus, the development of tailored
                      antiviral medications for patients with incomplete,
                      inefficient, or non-existent immunization, is essential. The
                      attachment of viral surface proteins to the cell surface is
                      the first crucial step in the viral replication cycle, which
                      for SARS-CoV-2 is mediated by the high affinity interaction
                      of the viral trimeric spike with the host cell
                      surface-located human angiotensin converting enzyme-2
                      (hACE2). Here, we used a novel and efficient next generation
                      sequencing (NGS) supported phage display strategy for the
                      selection of a set of SARS-CoV-2 receptor binding domain
                      (RBD)-targeting peptide ligands that bind to the target
                      protein with low µM to nM dissociation constants. Compound
                      CVRBDL-3 inhibits the SARS-CoV-2 spike protein association
                      to hACE2 in a concentration-dependent manner for pre- as
                      well as post-complex formation conditions. Further rational
                      optimization yielded a CVRBDL-3 based divalent compound,
                      which demonstrated inhibitory efficacy with an IC50 value of
                      47 nM. The obtained compounds were not only efficient for
                      the different spike constructs from the originally isolated
                      “wt” SARS-CoV-2, but also for B.1.1.7 mutant trimeric
                      spike protein. Our work demonstrates that phage
                      display-derived peptide ligands are potential fusion
                      inhibitors of viral cell entry. Moreover, we show that
                      rational optimization of a combination of peptide sequences
                      is a potential strategy in the further development of
                      therapeutics for the treatment of acute COVID-19.},
      cin          = {IBI-7},
      ddc          = {570},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5244 - Information Processing in Neuronal Networks
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5244},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {35203649},
      UT           = {WOS:000763798500001},
      doi          = {10.3390/biomedicines10020441},
      url          = {https://juser.fz-juelich.de/record/906319},
}