title: Double-clicking peptides onto phosphorothioate oligonucleotides: combining two proapoptotic agents in one molecule.
abstract: 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).
authors.affiliation: Department of Chemistry, Humboldt University Berlin, Brook-Taylor-Strasse 2, 12489 Berlin (Germany).
authors.forename: Frank
authors.initials: F
authors.lastname: Abendroth
authors.forename: Oliver
authors.initials: O
authors.lastname: Seitz
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001483:Base Sequence; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D061565:Cycloaddition Reaction; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000737:chemistry*; D010091:Oximes / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D010710:Phosphates / Q000737:chemistry*; D012333:RNA, Messenger / Q000737:chemistry; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D016376:Oligonucleotides, Antisense; D010091:Oximes; D010455:Peptides; D010710:Phosphates; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C083120:phosphorodithioic acid
keywords: DNA nanotechnology; antisense; apoptosis; click chemistry; synthetic methods