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PreprintCC BYChemRxiv

Development of oligo-thioester precursors for native chemical ligation of oligo-protein conjugates.

  • Albert Kakkis1
  • Sorina Chiorean1
  • Youlin Guo1
  • Jason Lee2
  • Quynh Nguyen Wong2
  • Brandon J. Orzolek2
  • Stephen E. Mercer3
  • Thomas McDonagh3
  • Richard E. Olson3
  • Sayumi Yamazoe4
  • Philip E. Dawson1
4 affiliations
  1. 1Department of Chemistry, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, 92037
  2. 2Automated Synthesis Facility, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, 92037
  3. 3Bristol Myers Squibb, 250 Water Street, Cambridge, MA, 02141
  4. 4Bristol Myers Squibb, 1000 Sierra Point Pkwy, Brisbane, CA, 94005
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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.

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Cite

BibTeXRIS
BibTeX
@misc{kakkis2026development,
  title = {{Development of oligo-thioester precursors for native chemical ligation of oligo-protein conjugates.}},
  author = {Albert Kakkis and Sorina Chiorean and Youlin Guo and Jason Lee and Quynh Nguyen Wong and Brandon J. Orzolek and Stephen E. Mercer and Thomas McDonagh and Richard E. Olson and Sayumi Yamazoe and Philip E. Dawson},
  howpublished = {ChemRxiv},
  year = {2026},
  month = oct,
  doi = {10.26434/chemrxiv.15010945/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010945/v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Development of oligo-thioester precursors for native chemical ligation of oligo-protein conjugates.
AU  - Albert Kakkis
AU  - Sorina Chiorean
AU  - Youlin Guo
AU  - Jason Lee
AU  - Quynh Nguyen Wong
AU  - Brandon J. Orzolek
AU  - Stephen E. Mercer
AU  - Thomas McDonagh
AU  - Richard E. Olson
AU  - Sayumi Yamazoe
AU  - Philip E. Dawson
PY  - 2026
DA  - 2026/10/23
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15010945/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010945/v1
AB  - 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.
ER  -