期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 59, 期 34, 页码 14246-14250出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202000837
关键词
bioorthogonal chemistry; N-acylthiazolidine; N-terminal cysteine; protein conjugation; protein modification
资金
- National Science Foundation
- National Institutes of Health [CHE-1904874, R01GM102735]
We report a novel conjugation of N-terminal cysteines (NCys) that proceeds with fast kinetics and exquisite selectivity, thereby enabling facile modification of NCys-bearing proteins in complex biological milieu. This new NCys conjugation proceeds via a thiazolidine boronate (TzB) intermediate that results from fast (k(2): approximate to 5000 m(-1) s(-1)) and reversible conjugation of NCys with 2-formylphenylboronic acid (FPBA). We designed a FPBA derivative that upon TzB formation elicits intramolecular acyl transfer to give N-acyl thiazolidines. In contrast to the quick hydrolysis of TzB, the N-acylated thiazolidines exhibit robust stability under physiologic conditions. The utility of the TzB-mediated NCys conjugation is demonstrated by rapid and non-disruptive labeling of two enzymes. Furthermore, applying this chemistry to bacteriophage allows facile chemical modification of phage libraries, which greatly expands the chemical space amenable to phage display.
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