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Peer-reviewedCC BY-NCScience Advances

Silver(I)-mediated amide-to-ester transformation on unprotected peptides for protein chemical synthesis and engineering

  • Zhenquan Sun1
  • Wai Yin Yau2,3
  • Huajie Kang2,3
  • Haiyan Zhou1
  • Xin Liu4
  • Zhibo Han4
  • Hongxiang Wu2,3,4
  • Xuechen Li1,5,6
6 affiliations
  1. 1Department of Chemistry, State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. China.
  2. 2Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, P. R. China.
  3. 3University of Chinese Academy of Sciences, Beijing 100049, P. R. China.
  4. 4School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, P. R. China.
  5. 5Materials Innovation Institute for Life Sciences and Energy (MILES), HKU-SIRI, Shenzhen, Guangdong 518000, P. R. China.
  6. 6Shanghai–Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. China.
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Abstract

Chemical protein synthesis has transformed the preparation of homogeneous peptides and proteins with site-specific modifications. Serine/threonine ligation offers a practical route to access difficult peptides and proteins via its aggregation-breaking intermediate, yet the preparation and regeneration of the prerequisite peptidyl salicylaldehyde ester still require the development of more efficient chemistry. Here, we report a silver(I)-mediated amide-to-ester transformation on unprotected peptides, enabled by an easily introduced N , S -benzylidene thioacetal scaffold. This method can chemoselectively convert backbone amides into salicylaldehyde esters in aqueous acetic acid without detectable epimerization, which is demonstrated by comprehensive syntheses of various peptide examples, the efficient total synthesis of mirror-image histones histone 2A (H2A), H2B, H3, and H4, and detailed mechanistic studies. This strategy establishes a general organic platform for programmable amide activation at the peptide or protein level.

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Cite

BibTeXRIS
BibTeX
@article{sun2026silverimediated,
  title = {{Silver(I)-mediated amide-to-ester transformation on unprotected peptides for protein chemical synthesis and engineering}},
  author = {Zhenquan Sun and Wai Yin Yau and Huajie Kang and Haiyan Zhou and Xin Liu and Zhibo Han and Hongxiang Wu and Xuechen Li},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aej5227},
  url = {https://www.science.org/doi/10.1126/sciadv.aej5227},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Silver(I)-mediated amide-to-ester transformation on unprotected peptides for protein chemical synthesis and engineering
AU  - Zhenquan Sun
AU  - Wai Yin Yau
AU  - Huajie Kang
AU  - Haiyan Zhou
AU  - Xin Liu
AU  - Zhibo Han
AU  - Hongxiang Wu
AU  - Xuechen Li
PY  - 2026
DA  - 2026/10/02
JO  - Science Advances
DO  - 10.1126/sciadv.aej5227
UR  - https://www.science.org/doi/10.1126/sciadv.aej5227
AB  - Chemical protein synthesis has transformed the preparation of homogeneous peptides and proteins with site-specific modifications. Serine/threonine ligation offers a practical route to access difficult peptides and proteins via its aggregation-breaking intermediate, yet the preparation and regeneration of the prerequisite peptidyl salicylaldehyde ester still require the development of more efficient chemistry. Here, we report a silver(I)-mediated amide-to-ester transformation on unprotected peptides, enabled by an easily introduced N , S -benzylidene thioacetal scaffold. This method can chemoselectively convert backbone amides into salicylaldehyde esters in aqueous acetic acid without detectable epimerization, which is demonstrated by comprehensive syntheses of various peptide examples, the efficient total synthesis of mirror-image histones histone 2A (H2A), H2B, H3, and H4, and detailed mechanistic studies. This strategy establishes a general organic platform for programmable amide activation at the peptide or protein level.
SN  - 2375-2548
ER  -