Double-Clicking Peptides onto Phosphorothioate Oligonucleotides: Combining Two Proapoptotic Agents in One Molecule

被引：15

作者：

Abendroth, Frank ^{[1
]}

Seitz, Oliver ^{[1
]}

机构：

[1] Humboldt Univ, Dept Chem, D-12489 Berlin, Germany

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2014年 / 53卷 / 39期

关键词：

antisense; apoptosis; click chemistry; DNA nanotechnology; synthetic methods; ANTISENSE OLIGONUCLEOTIDES; EFFICIENT SYNTHESIS; RNA INTERFERENCE; COPPER-FREE; THERAPEUTICS; CONJUGATION; NUCLEOSIDE; MECHANISMS; CHEMISTRY; APOPTOSIS;

D O I：

10.1002/anie.201406674

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Described here is a method for the conjugation of phosphorothioate oligonucleotides (PSOs) with peptides. PSOs are key to antisense technology. Peptide-PSO conjugates may improve target specificity, tissue distribution, and cellular uptake of PSOs. However, the highly nucleophilic phosphorothioate structure poses a challenge to conjugation chemistry. Herein, we introduce a new method which involves a sequence of oxime ligation and strain-promoted [2+3] cycloaddition. The usefulness of the method was demonstrated in the synthesis of peptide-PSO conjugates that targeted two suppressors of both the intrinsic and the extrinsic pathway of apoptosis. It is shown that the activity of a PSO sequence targeted against mRNA from c-Flip can be enhanced by conjugation with a peptide mimetic designed to inhibit the X-linked inhibitor of apoptosis protein (XIAP).

引用

页码：10504 / 10509

页数：6

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[1] DNA-Controlled Bivalent Presentation of Ligands for the Estrogen Receptor [J].