{
  "abstract": "Protein-oligo conjugates have emerged as a promising therapeutic modality that unites the target-specificity and favorable pharmacokinetics of a protein carrier with the potency of an oligonucleotide payload. One challenge in the development of these biologics is that conjugation strategies often yield heterogeneous, high drug-to-antibody ratio (DAR) products or require non-canonical amino acids and multi-step handling. Native chemical ligation (NCL) is a promising tool for protein-oligo conjugation, as the reaction is single-step and regiospecific to N-terminal cysteines, which can be genetically installed into proteins in a facile manner. However, methods for generating the required oligo-thioesters remain a technical challenge, especially when complex linker groups are desired. Here, we report an efficient protocol to generate four oligo linker-payloads (LPs) incorporating an anti-sense oligonucleotide targeting the MALAT1 gene, bis(2-sulfanylethyl)amine (NSS)- or thioacid-based thioester precursors, and diverse intervening linkers. The LPs were successfully ligated to an affibody and the crystallizable fragment (Fc) of an antibody, key protein carriers for protein-oligo therapeutics. The operationally simple, bespoke nature of this workflow enables the diversification of oligo payloads and linkers required for broad applications.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, 92037",
    "Automated Synthesis Facility, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, 92037",
    "Bristol Myers Squibb, 250 Water Street, Cambridge, MA, 02141",
    "Bristol Myers Squibb, 1000 Sierra Point Pkwy, Brisbane, CA, 94005"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Albert Kakkis",
      "orcid": "0000-0001-6225-7352"
    },
    {
      "affs": [
        0
      ],
      "name": "Sorina Chiorean",
      "orcid": "0000-0003-4801-7445"
    },
    {
      "affs": [
        0
      ],
      "name": "Youlin Guo"
    },
    {
      "affs": [
        1
      ],
      "name": "Jason Lee",
      "orcid": "0009-0001-4575-9040"
    },
    {
      "affs": [
        1
      ],
      "name": "Quynh Nguyen Wong",
      "orcid": "0009-0003-4305-6709"
    },
    {
      "affs": [
        1
      ],
      "name": "Brandon J. Orzolek",
      "orcid": "0000-0001-8160-5244"
    },
    {
      "affs": [
        2
      ],
      "name": "Stephen E. Mercer"
    },
    {
      "affs": [
        2
      ],
      "name": "Thomas McDonagh",
      "orcid": "0000-0002-1920-1086"
    },
    {
      "affs": [
        2
      ],
      "name": "Richard E. Olson"
    },
    {
      "affs": [
        3
      ],
      "name": "Sayumi Yamazoe",
      "orcid": "0000-0002-2169-7674"
    },
    {
      "affs": [
        0
      ],
      "name": "Philip E. Dawson",
      "orcid": "0000-0002-2538-603X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fg16g2v2kbm5t.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15010945/v1",
  "fulltext_url": null,
  "id": "fg16g2v2kbm5t",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010945/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": "W7223394309",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15010945/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-23",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/fg16g2v2kbm5t.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:26Z",
      "native_id": "10.26434/chemrxiv.15010945",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010945/v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Chemical Synthesis and Analysis",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Development of oligo-thioester precursors for native chemical ligation of oligo-protein conjugates.",
  "title_text": "Development of oligo-thioester precursors for native chemical ligation of oligo-protein conjugates.",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:26Z",
  "url": "https://research.draconitic.com/paper/fg16g2v2kbm5t",
  "venue": "ChemRxiv",
  "versions": []
}