Double-Clicking Peptides onto Phosphorothioate Oligonucleotides: Combining Two Proapoptotic Agents in One Molecule
Frank Abendroth and Oliver Seitz – 2014
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).