{
  "abstract": "Macrocyclic peptides possess numerous advantages, including enhanced tissue penetration, low immunogenicity, good resistance to protease degradation, and high targeting specificity, making them increasingly attractive for drug development. Genetically encoded cyclic peptide libraries enable rapid and convenient de novo discovery of cyclic peptide lead compounds, avoiding the tedious and time-consuming process of isolating natural cyclic peptides. In genetically encoded cyclic peptide libraries, the construction of cyclic peptide frameworks typically requires bioorthogonal reactions to cyclize peptides generated by phages or mRNA. The diversity of the cyclic peptide framework is limited by the type of cyclization reaction. Late-stage cysteine crosslinking is a convenient method for constructing genetically encoded cyclic peptides with different cyclic frameworks. However, enzyme-free cyclization strategies, while versatile, are generally constrained by inherent trade-offs among reaction kinetics, chemoselectivity, and biocompatibility—factors that become particularly critical when preserving the functional integrity of the genetic payload in display platforms. Sortase-mediated peptide ligation and one-pot cyclization (SPLOC) is a mild chemoenzymatic modification strategy that utilizes sortase to introduce a low-reactivity chloroacetyl group into phage-displayed peptides, followed by intramolecular cyclization with a cysteine residue to generate cyclic peptides. Previous sortase-based platforms only used the chloroacetyl group, limiting exploration of a broad chemical space. In this study, we designed and synthesized a series of low-reactivity electrophilic peptide substrates, tested their compatibility with sortase, and generated various cyclic peptide frameworks. Combined with phage display, we discovered several cyclic peptide ligands targeting human IgG1 Fc protein and TROP2, demonstrating the practicality of our approach. The finding of the compatibility of sortase with various low-reactivity electrophilic peptide substrates will provide a useful chemoenzymatic method for constructing cyclic peptide libraries with diverse frameworks.",
  "abstract_shown": true,
  "affiliations": [
    "High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences Hefei 230031 P. R. China",
    "School of Life Sciences and Medical Engineering, Anhui University Hefei 230601 P.R. China",
    "Anhui Provincial Peptide Drug Engineering Laboratory, Hefei KS-V Peptide Biological Technology Co., Ltd P. R. China",
    "School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China Hefei 230026 P. R. China",
    "School of Chemistry and Chemical Engineering, ZhangJiang Institute for Advanced Study, Shanghai Jiao Tong University Shanghai 201204 China",
    "Beijing Life Science Academy Beijing China 102209"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Zhe-Min Xia"
    },
    {
      "affs": [
        1
      ],
      "name": "Hui-Min Wei"
    },
    {
      "affs": [
        1
      ],
      "name": "Jun-Hao Xue"
    },
    {
      "affs": [
        1
      ],
      "name": "Ya-Ning Sun"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiao-Cui Wan"
    },
    {
      "affs": [
        2
      ],
      "name": "Hua-Rong Tong"
    },
    {
      "affs": [
        2
      ],
      "name": "Li Zhou"
    },
    {
      "affs": [
        3
      ],
      "name": "Pan Shi"
    },
    {
      "affs": [
        1
      ],
      "name": "Ge-Min Fang",
      "orcid": "0000-0003-4149-4062"
    },
    {
      "affs": [
        0,
        3,
        4,
        5
      ],
      "name": "Changlin Tian",
      "orcid": "0000-0001-9315-900X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/d9kt4h6v4kjrw.bib",
  "cited_by": 0,
  "doi": "10.1039/d6sc03710k",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13575866/",
  "id": "d9kt4h6v4kjrw",
  "issns": [
    "2041-6520",
    "2041-6539"
  ],
  "landing_url": "https://doi.org/10.1039/d6sc03710k",
  "language": "en",
  "licence": "CC-BY-NC-3.0",
  "licence_label": "CC BY-NC 3.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/3.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Chemistry"
    ],
    [
      "openalex",
      "1312|Biochemical and Structural Characterization"
    ]
  ],
  "openalex": "W7208731849",
  "pdf_url": null,
  "pmcid": "PMC13575866",
  "pmid": "42746122",
  "published": "2026-09-04",
  "publisher": "Royal Society of Chemistry",
  "ris": "https://research.draconitic.com/paper/d9kt4h6v4kjrw.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T12:23:29Z",
      "native_id": "PMC13575866",
      "source": "pmc",
      "url": "https://doi.org/10.1039/d6sc03710k"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Biochemical and Structural Characterization",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Sortase-mediated generation of various macrocyclic peptide scaffolds from low-reactivity electrophilic substrates",
  "title_text": "Sortase-mediated generation of various macrocyclic peptide scaffolds from low-reactivity electrophilic substrates",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T12:20:58Z",
  "url": "https://research.draconitic.com/paper/d9kt4h6v4kjrw",
  "venue": "Chemical Science",
  "versions": []
}