• Genetic Code Expansion in Prob...

Treffer: Genetic Code Expansion in Probiotics Enables the Secretion of Covalent Protein Drugs in Mice.

Title:
Genetic Code Expansion in Probiotics Enables the Secretion of Covalent Protein Drugs in Mice.
Authors:
Wang K; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China., Wu Y; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China., Shang J; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China., Bu L; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China., Hu D; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China., He H; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China., Wang R; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China., Mao J; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China., Yan Y; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China., Guan J; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China., Wang R; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences and Research Unit of Peptide Science, Chinese Academy of Medical Sciences, Lanzhou University, Lanzhou 730000, China., Luo H; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Source:
Journal of the American Chemical Society [J Am Chem Soc] 2026 Jan 14; Vol. 148 (1), pp. 1397-1405. Date of Electronic Publication: 2025 Dec 22.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: American Chemical Society Country of Publication: United States NLM ID: 7503056 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5126 (Electronic) Linking ISSN: 00027863 NLM ISO Abbreviation: J Am Chem Soc Subsets: MEDLINE
Imprint Name(s):
Publication: Washington, DC : American Chemical Society
Original Publication: Easton, Pa. [etc.]
MeSH Terms:
Probiotics*/administration & dosage , Genetic Code* , Escherichia coli*/genetics , Escherichia coli*/metabolism , Tyrosine*/analogs & derivatives , Tyrosine*/metabolism , Tyrosine*/genetics, Animals ; Mice ; Colitis/drug therapy ; Administration, Oral
Substance Nomenclature:
42HK56048U (Tyrosine)
Entry Date(s):
Date Created: 20251222 Date Completed: 20260115 Latest Revision: 20260115
Update Code:
20260115
DOI:
10.1021/jacs.5c17978
PMID:
41428953
Database:
MEDLINE

Weitere Informationen

Oral delivery of therapeutic proteins remains a formidable challenge. Although engineered microbes have emerged as promising platforms for localized drug synthesis in the gut, their functional capacity has been restricted to the 20 canonical amino acids, limiting the chemical diversity of biologic payloads. Here, we demonstrate that integrating genetic code expansion (GCE) into bacterial therapy overcomes this fundamental constraint. We engineered the probiotic Escherichia coli Nissle 1917 (EcN) to incorporate the noncanonical amino acid fluorosulfate-l-tyrosine (FSY), enabling in situ secretion of a site-specifically modified covalent anti-IL-23 nanobody exhibiting picomolar binding potency (5.9 pM). Oral administration of this engineered EcN strain, followed by FSY supplementation, significantly ameliorated colitis in a murine model. This approach thereby establishes a versatile and generalizable platform that substantially expands the functional scope and therapeutic potential of live biotherapeutics.