title: A method for solid-phase synthesis of oligonucleotide 5'-peptide-conjugates using acid-labile alpha-amino protections.
abstract: We describe the development of a solid-phase technique for the synthesis of 5'-peptide-oligonucleotide conjugates (POCs) with a uniform protection strategy for the nucleic acid and the peptide fragments. On the alpha-amino function, the amino acid building blocks were protected with the 2-(biphenyl-4-yl)propan-2-yloxycarbonyl (Bpoc) group. This protection is removed during the stepwise peptide elongation by the same acidic conditions used for removal of the dimethoxytrityl (DMT) group used in the oligonucleotide assembly (3% trichloroacetic acid, 2 min). The 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl (Ddz) group was also tested. With this somewhat more stable group, a prolonged contact with the acid (at least 16 min) was required for accomplishing complete alpha-amino deprotection, which resulted in some degree of depurination of the acid-sensitive DNA chain. Base-labile acyl protections were adopted for the side-chains of histidine, lysine, and the nucleobase amino functions. These were all removed in the final deblocking step by ammonolysis. This uniform protection scheme for the peptide and the oligonucleotide enabled the total stepwise synthesis of model conjugates in the 3' --> N direction with high efficiency and purity.
authors.affiliation: Division of Organic and Bioorganic Chemistry, MBB, Scheele Laboratory, Karolinska Institutet, S-17177 Stockholm, Sweden.
authors.forename: Simone
authors.initials: S
authors.lastname: Zaramella
authors.forename: Esther
authors.initials: E
authors.lastname: Yeheskiely
authors.forename: Roger
authors.initials: R
authors.lastname: Strömberg
mesh_terms: D000215:Acylation; D002625:Chemistry, Organic / Q000379:methods; D009841:Oligonucleotides / Q000138:chemical synthesis*; D010455:Peptides / Q000138:chemical synthesis*
chemical_list: D009841:Oligonucleotides; D010455:Peptides