{
  "abstract": "Microbial transglutaminase (mTGase) readily forms intermolecular isopeptide bonds, but this native bias promotes peptide oligomerization at synthetically useful concentrations. Here we encode reaction topology in a minimal diamine linker to redirect mTGase toward intramolecular stapling of unprotected glutamine-containing peptides. Direct comparison with a linker-free Lys–Gln substrate shows that the linker-encoded architecture maintains macrocyclization as the dominant pathway from 0.25 to 2.0 mM, whereas the native substrate undergoes exclusively intermolecular ligation. Linker and peptide studies establish geometric, electronic, and sequence requirements, and molecular simulations are consistent with the organization of the acyl–enzyme intermediate. The resulting staples serve as versatile synthetic handles for orthogonal bicyclization, late-stage functionalization, and reductive ring opening. The covalent immobilization of mTGase enables catalyst recycling and seamless integration into a continuous, automated peptide-stapling platform capable of processing diverse substrates. This linker-encoded strategy provides a route to control enzymatic reaction topology for programmable constrained-peptide synthesis.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "name": "Wanglin Zhan"
    },
    {
      "name": "Cheng Fan"
    },
    {
      "name": "Chengrui Hu"
    },
    {
      "name": "Chengxi Li",
      "orcid": "0000-0003-3904-0299"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ahg721tma6056.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15009690/v1",
  "fulltext_url": null,
  "id": "ahg721tma6056",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009690/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Chemical Synthesis and Analysis"
    ]
  ],
  "openalex": "W7214974254",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15009690/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-30",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/ahg721tma6056.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:21Z",
      "native_id": "10.26434/chemrxiv.15009690",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009690/v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Chemical Synthesis and Analysis",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Linker-Encoded Enzymatic Topology Control Enables Automated Peptide Stapling with Reusable Immobilized mTGase",
  "title_text": "Linker-Encoded Enzymatic Topology Control Enables Automated Peptide Stapling with Reusable Immobilized mTGase",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:21Z",
  "url": "https://research.draconitic.com/paper/ahg721tma6056",
  "venue": "ChemRxiv",
  "versions": []
}