化学
衍生化
多粘菌素
组合化学
肽
苏氨酸
酰化
丝氨酸
氨基酸
残留物(化学)
生物化学
有机化学
抗生素
催化作用
酶
高效液相色谱法
作者
Rintaro Kaguchi,Akira Katsuyama,Toyotaka Sato,Satoshi Takahashi,Motohiro Horiuchi,Shin‐ichi Yokota,Satoshi Ichikawa
摘要
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.
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