{
  "abstract": "Peptide macrocyclization is a powerful strategy to enhance the stability, rigidity, binding affinity, and cellular permeability of therapeutic candidates. Peptide bicycles provide superior conformational constraint but remain difficult to generate in phage-displayed libraries because of limited phage-compatible chemistries. Here, we report Proximity-Driven, Regioselective Peptide Bicyclization (PReP-Bicyc), a general, additive-free, phage-compatible strategy for site-selective bicyclization of peptide libraries. PReP-Bicyc uses a rationally designed linker, 4,6-dichloropyrimidine-2-carbonitrile (4,6-DCCPm), that rapidly reacts with an N-terminal cysteine through nitrile-mediated thiazoline formation, followed by proximity-driven intramolecular thiol arylation of two internal cysteines. The resulting bicycles form efficiently under mild conditions while preserving phage viability. Screening a PReP-Bicyc-modified CX₄CX₄C library against programmed cell death protein 1 (PD-1) identifies sub-micromolar bicyclic ligands (best Kd ≈ 400 nM) that selectively label PD-1-expressing cells and inhibit the PD-1/PD-L1 interaction. PReP-Bicyc provides a robust platform for evolving high-affinity bicyclic ligands and expands the chemical toolkit for macrocyclic therapeutic discovery.",
  "abstract_shown": true,
  "affiliations": [
    "Texas A&M Drug Discovery Center and Department of Chemistry, College of Arts and Sciences, Texas A&M University, College Station, TX, USA.",
    "Institute of Biosciences and Technology and Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, USA.",
    "Texas A&M Drug Discovery Center and Department of Chemistry, College of Arts and Sciences, Texas A&M University, College Station, TX, USA. jhampton1@tamu.edu.",
    "Texas A&M Drug Discovery Center and Department of Chemistry, College of Arts and Sciences, Texas A&M University, College Station, TX, USA. wsliu2007@tamu.edu.",
    "Institute of Biosciences and Technology and Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, USA. wsliu2007@tamu.edu.",
    "Department of Biochemistry and Biophysics, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX, USA. wsliu2007@tamu.edu.",
    "Department of Cell Biology and Genetics, College of Medicine, Texas A&M University, College Station, TX, USA. wsliu2007@tamu.edu.",
    "Department of Pharmaceutical Sciences, Lerma Rangel College of Pharmacy, Texas A&M University, College Station, TX, USA. wsliu2007@tamu.edu."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Guoqing Jin",
      "orcid": "0000-0001-9795-0149"
    },
    {
      "affs": [
        0
      ],
      "name": "Yifan Shi"
    },
    {
      "affs": [
        0
      ],
      "name": "Shihui Fan"
    },
    {
      "affs": [
        0
      ],
      "name": "Lai Hoang Son Le",
      "orcid": "0000-0002-2473-6309"
    },
    {
      "affs": [
        1
      ],
      "name": "Wenyue Cao",
      "orcid": "0000-0001-8718-6634"
    },
    {
      "affs": [
        1
      ],
      "name": "Thuzar Hla Shwe"
    },
    {
      "affs": [
        1
      ],
      "name": "Zihan Anna Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Demonta D Coleman"
    },
    {
      "affs": [
        0
      ],
      "name": "Satyanarayana Nyalata"
    },
    {
      "affs": [
        2
      ],
      "name": "Joshua Trae Hampton",
      "orcid": "0000-0001-5562-162X"
    },
    {
      "affs": [
        3,
        4,
        5,
        6,
        7
      ],
      "name": "Wenshe Ray Liu",
      "orcid": "0000-0002-7078-6534"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3rd70t1g2qry5.bib",
  "cited_by": 0,
  "doi": "10.1038/s41467-026-77740-5",
  "fulltext_url": "https://europepmc.org/articles/PMC13724736",
  "id": "3rd70t1g2qry5",
  "issns": [
    "2041-1723"
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  "landing_url": "https://www.nature.com/articles/s41467-026-77740-5",
  "language": "eng",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0",
  "metadata_licence": null,
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      "1312|Chemical Synthesis and Analysis"
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  "pdf_url": "https://www.nature.com/articles/s41467-026-77740-5_reference.pdf",
  "pmcid": "PMC13724736",
  "pmid": "42967907",
  "published": "2026-10-03",
  "publisher": "Springer Science and Business Media LLC",
  "ris": "https://research.draconitic.com/paper/3rd70t1g2qry5.ris",
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Chemical Synthesis and Analysis",
      "subfield": "molecular-biology"
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  ],
  "title": "A proximity-driven and regioselective peptide bicyclization (PReP-Bicyc) approach for phage display libraries",
  "title_text": "A proximity-driven and regioselective peptide bicyclization (PReP-Bicyc) approach for phage display libraries",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:21:08Z",
  "url": "https://research.draconitic.com/paper/3rd70t1g2qry5",
  "venue": "Nature Communications",
  "versions": []
}