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Peer-reviewedCC BY-NC 3.0Chemical Science

Sortase-mediated generation of various macrocyclic peptide scaffolds from low-reactivity electrophilic substrates

  • Zhe-Min Xia1
  • Hui-Min Wei2
  • Jun-Hao Xue2
  • Ya-Ning Sun2
  • Xiao-Cui Wan2
  • Hua-Rong Tong3
  • Li Zhou3
  • Pan Shi4
  • Ge-Min Fang2
  • Changlin Tian1,4,5,6
6 affiliations
  1. 1High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences Hefei 230031 P. R. China
  2. 2School of Life Sciences and Medical Engineering, Anhui University Hefei 230601 P.R. China
  3. 3Anhui Provincial Peptide Drug Engineering Laboratory, Hefei KS-V Peptide Biological Technology Co., Ltd P. R. China
  4. 4School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China Hefei 230026 P. R. China
  5. 5School of Chemistry and Chemical Engineering, ZhangJiang Institute for Advanced Study, Shanghai Jiao Tong University Shanghai 201204 China
  6. 6Beijing Life Science Academy Beijing China 102209
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Abstract

Macrocyclic peptides possess numerous advantages, including enhanced tissue penetration, low immunogenicity, good resistance to protease degradation, and high targeting specificity, making them increasingly attractive for drug development. Genetically encoded cyclic peptide libraries enable rapid and convenient de novo discovery of cyclic peptide lead compounds, avoiding the tedious and time-consuming process of isolating natural cyclic peptides. In genetically encoded cyclic peptide libraries, the construction of cyclic peptide frameworks typically requires bioorthogonal reactions to cyclize peptides generated by phages or mRNA. The diversity of the cyclic peptide framework is limited by the type of cyclization reaction. Late-stage cysteine crosslinking is a convenient method for constructing genetically encoded cyclic peptides with different cyclic frameworks. However, enzyme-free cyclization strategies, while versatile, are generally constrained by inherent trade-offs among reaction kinetics, chemoselectivity, and biocompatibility—factors that become particularly critical when preserving the functional integrity of the genetic payload in display platforms. Sortase-mediated peptide ligation and one-pot cyclization (SPLOC) is a mild chemoenzymatic modification strategy that utilizes sortase to introduce a low-reactivity chloroacetyl group into phage-displayed peptides, followed by intramolecular cyclization with a cysteine residue to generate cyclic peptides. Previous sortase-based platforms only used the chloroacetyl group, limiting exploration of a broad chemical space. In this study, we designed and synthesized a series of low-reactivity electrophilic peptide substrates, tested their compatibility with sortase, and generated various cyclic peptide frameworks. Combined with phage display, we discovered several cyclic peptide ligands targeting human IgG1 Fc protein and TROP2, demonstrating the practicality of our approach. The finding of the compatibility of sortase with various low-reactivity electrophilic peptide substrates will provide a useful chemoenzymatic method for constructing cyclic peptide libraries with diverse frameworks.

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Cite

BibTeXRIS
BibTeX
@article{xia2026sortasemediated,
  title = {{Sortase-mediated generation of various macrocyclic peptide scaffolds from low-reactivity electrophilic substrates}},
  author = {Zhe-Min Xia and Hui-Min Wei and Jun-Hao Xue and Ya-Ning Sun and Xiao-Cui Wan and Hua-Rong Tong and Li Zhou and Pan Shi and Ge-Min Fang and Changlin Tian},
  journal = {Chemical Science},
  year = {2026},
  month = sep,
  doi = {10.1039/d6sc03710k},
  url = {https://doi.org/10.1039/d6sc03710k},
  note = {CC BY-NC 3.0},
}
RIS
TY  - JOUR
TI  - Sortase-mediated generation of various macrocyclic peptide scaffolds from low-reactivity electrophilic substrates
AU  - Zhe-Min Xia
AU  - Hui-Min Wei
AU  - Jun-Hao Xue
AU  - Ya-Ning Sun
AU  - Xiao-Cui Wan
AU  - Hua-Rong Tong
AU  - Li Zhou
AU  - Pan Shi
AU  - Ge-Min Fang
AU  - Changlin Tian
PY  - 2026
DA  - 2026/09/04
JO  - Chemical Science
DO  - 10.1039/d6sc03710k
UR  - https://doi.org/10.1039/d6sc03710k
AB  - Macrocyclic peptides possess numerous advantages, including enhanced tissue penetration, low immunogenicity, good resistance to protease degradation, and high targeting specificity, making them increasingly attractive for drug development. Genetically encoded cyclic peptide libraries enable rapid and convenient de novo discovery of cyclic peptide lead compounds, avoiding the tedious and time-consuming process of isolating natural cyclic peptides. In genetically encoded cyclic peptide libraries, the construction of cyclic peptide frameworks typically requires bioorthogonal reactions to cyclize peptides generated by phages or mRNA. The diversity of the cyclic peptide framework is limited by the type of cyclization reaction. Late-stage cysteine crosslinking is a convenient method for constructing genetically encoded cyclic peptides with different cyclic frameworks. However, enzyme-free cyclization strategies, while versatile, are generally constrained by inherent trade-offs among reaction kinetics, chemoselectivity, and biocompatibility—factors that become particularly critical when preserving the functional integrity of the genetic payload in display platforms. Sortase-mediated peptide ligation and one-pot cyclization (SPLOC) is a mild chemoenzymatic modification strategy that utilizes sortase to introduce a low-reactivity chloroacetyl group into phage-displayed peptides, followed by intramolecular cyclization with a cysteine residue to generate cyclic peptides. Previous sortase-based platforms only used the chloroacetyl group, limiting exploration of a broad chemical space. In this study, we designed and synthesized a series of low-reactivity electrophilic peptide substrates, tested their compatibility with sortase, and generated various cyclic peptide frameworks. Combined with phage display, we discovered several cyclic peptide ligands targeting human IgG1 Fc protein and TROP2, demonstrating the practicality of our approach. The finding of the compatibility of sortase with various low-reactivity electrophilic peptide substrates will provide a useful chemoenzymatic method for constructing cyclic peptide libraries with diverse frameworks.
SN  - 2041-6520
SN  - 2041-6539
ER  -