{
  "abstract": "Native chemical ligation has transformed chemical protein synthesis, yet its reliance on C-terminal peptide thioesters suffers from precursor preparation, stability and multisegment assembly. Here we report peptide nitrile ligation (PNL), a thioester-free ligation in which a stable C-terminal peptide nitrile is chemoselectively captured by an N-terminal cysteine and converted through a thiazoline intermediate into a native Xaa-Cys amide bond. Peptide nitriles are generated directly and chemoselectively from the C-terminal amides obtained using conventional Rink-amide Fmoc solid-phase peptide synthesis. PNL proceeds in aqueous buffer at pH 7.5 without an exogenous thiol catalyst, a thioester intermediate or detectable epimerization at the ligation junction. Notably, PNL enables efficient ligation at C-terminal proline junctions, a longstanding challenge in thioester-based ligation, without specialized building blocks or additional synthetic steps. The reaction tolerates internal cysteine thiols and Asn- or Gln-derived side-chain nitriles, with the latter subsequently restored to their native amides. On-demand conversion of C-terminal amide into a new nitrile enables iterative three-segment assembly. PNL therefore establishes C-terminal nitriles as stable, programmable acyl donors for thioester-free multisegment peptide ligation.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry",
    "Emory University"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Bao Quang Gia Le"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Adrija Majumdar"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Abhisek Kar"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Shyla Singal"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Anvi Anand"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Monika Raj",
      "orcid": "0000-0001-9636-2222"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/emvgazj074r9z.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15011000/v1",
  "fulltext_url": null,
  "id": "emvgazj074r9z",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15011000/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": "W7223572733",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15011000/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-25",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/emvgazj074r9z.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:26Z",
      "native_id": "10.26434/chemrxiv.15011000",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15011000/v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Chemical Synthesis and Analysis",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Peptide nitrile ligation enables thioester-free chemical protein synthesis",
  "title_text": "Peptide nitrile ligation enables thioester-free chemical protein synthesis",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:26Z",
  "url": "https://research.draconitic.com/paper/emvgazj074r9z",
  "venue": "ChemRxiv",
  "versions": []
}