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  • [Mol Pharm.] Immunoglobulin Fc-Fused Peptide without C-Terminal Arg or Lys Residue Augments Neuropilin-1-Dependent Tumor Vascular Permeability.

    아주대 / 백두산, 김용성*

  • 출처
    Mol Pharm.
  • 등재일
    2018 Feb 5
  • 저널이슈번호
    15(2):394-402. doi: 10.1021/acs.molpharmaceut.7b00761. Epub 2017 Dec 21.
  • 내용

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    Abstract
    Neuropilin-1 (NRP1), which functions as a coreceptor for vascular endothelial growth factor (VEGF) and is implicated in vascular permeability and tumorigenesis, has been targeted by peptides that specifically bind to the VEGF-binding region on NRP1. Like natural VEGF ligands, all known peptides with NRP1-binding activity bind only through a carboxy (C)-terminal R/K-x-x-R/K sequence motif (x stands for any amino acids); this strict requirement is called the C-end rule (CendR). Here, we report immunoglobulin Fc-fused NRP1-specific peptides deviating from CendR. We screened a yeast surface-displayed Fc-fused non-CendR peptide library against NRP1 and isolated Fc-V12, wherein V12 peptide comprising 12 amino acids has a PPRV sequence at its C-terminal end. Although Fc-V12 lacked the CendR motif, it showed selective binding to the VEGF-binding region of NRP1 and triggered cellular internalization of NRP1, which resulted in enhanced extravasation into tumor tissues and tumor tissue penetration of the Fc-fused peptide along with the coinjected chemical drug in tumor-bearing mice. Through a saturation mutagenesis study, we identified that the Val residue at the C-terminus of Fc-V12 is crucial for NRP1 binding. We further improved NRP1 affinity of Fc-V12 (KD = ∼761 nM) through directed evolution of the upstream sequence of PPRV to obtain Fc-V12-33 (KD = ∼17.4 nM), which exhibited enhanced NRP1-mediated vascular permeability as compared with Fc-V12. Our results provide functional Fc-fused non-CendR peptides, which bind to the VEGF-binding region of NRP1 and enhance vascular permeability, expanding the sequence space of NRP1-targeting peptides.

     


    Author information

    Baek DS1, Kim JH1, Kim YJ1, Kim YS1.
    1
    Department of Molecular Science and Technology, Ajou University , Suwon 16499, Republic of Korea.

  • 키워드
    C-end rule; neuropilin-1; peptide engineering; vascular permeability; yeast surface display
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