发明名称 |
PICTET-SPENGLER LIGATION FOR PROTEIN CHEMICAL MODIFICATION |
摘要 |
Aldehyde- and ketone-functionalized proteins are promising new substrates for the development of chemically modified biotherapeutics and protein-based materials. Their reactive carbonyl groups are typically conjugated with a-effect nucleophiles, such as substituted hydrazines and alkoxyamines, to generate hydrazones and oximes, respectively. However, the resulting C═N linkages are susceptible to hydrolysis under physiologically relevant conditions, which limits their utility in biological systems. Here we introduce a Pictet-Spengler ligation that is based on the classic Pictet-Spengler reaction of aldehydes and tryptamine nucleophiles. The ligation exploits the bioorthogonal reaction of aldehydes and alkoxyamines to form an intermediate oxyiminium ion; this intermediate undergoes intramolecular C—C bond formation with an indole nucleophile to form an oxacarboline product that is hydrolytically stable. The reaction was utilized for site-specific chemical modification of glyoxal- and formylglycine-functionalized proteins, including an aldehyde-tagged variant of the therapeutic monoclonal antibody Herceptin. In conjunction with techniques for site-specific introduction of aldehydes into proteins, the Pictet-Spengler ligation offers a new means to generate stable bioconjugates for medical and materials applications. |
申请公布号 |
EP2920148(A1) |
申请公布日期 |
2015.09.23 |
申请号 |
EP20130855761 |
申请日期 |
2013.11.15 |
申请人 |
THE REGENTS OF THE UNIVERSITY OF CALIFORNIA |
发明人 |
BERTOZZI, CAROLYN;AGARWAL, PARESH;SLETTEN, ELLEN, M. |
分类号 |
C07D209/12;A61K39/385;C07D498/04 |
主分类号 |
C07D209/12 |
代理机构 |
|
代理人 |
|
主权项 |
|
地址 |
|