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PreprintCC BYChemRxiv

Chain-Growth Synthesis of Sequence-Defined Native Polypeptides via Traceless Cascade Polymerization

  • Jinxing Li1,2
  • Yuchen Ma1,2
  • Erika A. Ding3,2
  • Jonathan G. Mendes1,2
  • Zhenyu Han4,5
  • Ian M. Kish1,2
  • Thomas J. Emge1,2
  • Benjamin S. Schuster3,2
  • Yuwei Gu1,2
5 affiliations
  1. 1Department of Chemistry and Chemical Biology
  2. 2Rutgers, The State University of New Jersey
  3. 3Department of Chemical and Biochemical Engineering
  4. 4Wyss Institute for Biologically Inspired Engineering
  5. 5Harvard University
Open at sourceDOICite

Abstract

Despite sharing a common macromolecular foundation, synthetic polymers and sequencedefined biomacromolecules have historically evolved along distinct trajectories. Extending the principles of polymerization beyond synthetic materials to nature’s own sequence-defined polymers therefore remains a longstanding challenge. Here we address this challenge by developing a controlled chain-growth polymerization strategy for the synthesis of repetitive sequence-defined native polypeptides. A traceless peri-naphthalene cascade relays the propagating chain end while connecting peptide segments exclusively through native peptide bonds. The resulting synthetic polypeptides reproduce the sequence-dependent biophysical behavior of recombinant analogues while accommodating non-canonical α-, β-, and ᴅ-amino acids. This work fundamentally expands the molecular complexity accessible through controlled polymerization, placing sequence-defined native biomacromolecules within the same chain-growth paradigm as synthetic polymers.

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Cite

BibTeXRIS
BibTeX
@misc{li2026chaingrowth,
  title = {{Chain-Growth Synthesis of Sequence-Defined Native Polypeptides via Traceless Cascade Polymerization}},
  author = {Jinxing Li and Yuchen Ma and Erika A. Ding and Jonathan G. Mendes and Zhenyu Han and Ian M. Kish and Thomas J. Emge and Benjamin S. Schuster and Yuwei Gu},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15008205/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008205/v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Chain-Growth Synthesis of Sequence-Defined Native Polypeptides via Traceless Cascade Polymerization
AU  - Jinxing Li
AU  - Yuchen Ma
AU  - Erika A. Ding
AU  - Jonathan G. Mendes
AU  - Zhenyu Han
AU  - Ian M. Kish
AU  - Thomas J. Emge
AU  - Benjamin S. Schuster
AU  - Yuwei Gu
PY  - 2026
DA  - 2026/09/02
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15008205/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008205/v1
AB  - Despite sharing a common macromolecular foundation, synthetic polymers and sequencedefined biomacromolecules have historically evolved along distinct trajectories. Extending the principles of polymerization beyond synthetic materials to nature’s own sequence-defined polymers therefore remains a longstanding challenge. Here we address this challenge by developing a controlled chain-growth polymerization strategy for the synthesis of repetitive sequence-defined native polypeptides. A traceless peri-naphthalene cascade relays the propagating chain end while connecting peptide segments exclusively through native peptide bonds. The resulting synthetic polypeptides reproduce the sequence-dependent biophysical behavior of recombinant analogues while accommodating non-canonical α-, β-, and ᴅ-amino acids. This work fundamentally expands the molecular complexity accessible through controlled polymerization, placing sequence-defined native biomacromolecules within the same chain-growth paradigm as synthetic polymers.
ER  -