open access

https://hdl.handle.net/2115/91298

Discovery of Biologically Optimized Polymyxin Derivatives Facilitated by Peptide Scanning and In Situ Screening Chemistry

英語

2023-01-28

American Chemical Society

Journal of the American Chemical Society

145(6)

3665-3681

Peptides can be converted to highly active compounds by introducing appropriate substituents on the suitable amino acid residue. Although modifiable residues in peptides can be systematically identified by peptide scanning methodologies, there is no practical method for optimization at the scanned position. With the purpose of using derivatives not only for scanning but also as a starting point for further chemical functionalization, we herein report the scanning and direct derivatization strategy through chemoselective acylation of embedded threonine residues by a serine/threonine ligation (STL) with the help of in situ screening chemistry. We have applied this strategy to the optimization of the polymyxin antibiotics, which were selected as a model system to highlight the power of the rapid derivatization of active scanning derivatives. Using this approach, we explored the structure-activity relationships of the polymyxins and successfully prepared derivatives with activity against polymyxin-resistant bacteria and those with Pseudomonas aeruginosa selective antibacterial activity. This strategy opens up efficient structural exploration and further optimization of peptide sequences.

学術雑誌論文

Accepted Manuscript

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of the American Chemical Society, copyright c American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/articlesonrequest/AOR-XBYQEPWFHMMYJGTM6Z4I.

0002-7863