Chemoenzymatic Modification of Microcin J25 with Single-Residue Precision Provides New-to-Nature Lasso Peptides.

Authors

Chia-Yu Tsai, Hsueh-Wei Chung, Yi-Ping Huang, Chi-Fon Chang, Kwun-Yung Cheung, Hui-Ni Tan, Hsiao-Yun Huang, Li-Kang Sung, Julian D Hegemann, Yi-Tsu Chan, John Chu

Published in

JACS Au. Volume 6. Issue 8. Pages 4618-4625. Aug 24, 2026. Epub Aug 04, 2026.

Abstract

Reported herein is a new approach for constructing mechanically interlocked molecules based on the lasso peptide microcin J25 (MccJ25). Our approach began with site-selective proteolysis in the loop region of MccJ25, in which thermolysin hydrolyzed one or two specific amide bonds to create an incision or an excision, respectively, while preserving the macrolactam ring and the threaded architecture. Subsequent amide bond reformation, promoted by a peptide coupling reagent, resealed the incision and restored the lasso structure. We then added another level of complexity by incorporating diverse molecular building blocks into the proteolytically digested MccJ25 scaffold. Using this chemoenzymatic workflow, a series of new-to-nature lasso peptides was prepared. Specifically, we increased or decreased the size of the loop, incorporated noncanonical amino acids (AAs)including d-form and N-methylated AAsand even installed a bulky naphthalene moiety. This workflow opens new opportunities for developing functional materials for biomedical applications based on a lasso peptide scaffold.

PMID:
42657259
Bibliographic data and abstract were imported from PubMed on 18 Oct 2026.

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