A functionalized 20-residue peptaibol derivative for nucleic acid delivery.
Based on the membrane-modifying peptaibol trichocellin-A-I (1) from Trichoderma viride, we designed a vehicle for the cellular delivery of antisense oligodeoxynucleotides by attaching a (Lys)10 stretch to the C-terminus of 1. The resulting transporter peptide 2, prepared by solid-phase synthesis using Fmoc protocol in combination with amino acid fluorides, was found to be mainly alpha-helical in solution, in contrast to its precursors 1 and 3. The uptake of the complex formed between carrier 2 and a fluorescence-tagged oligonucleotide, i.e., 4, was studied at different charge ratios by confocal laser-scanning microscopy, using two different eukaryotic cell lines: mouse embryonal fibroblast (NIH3T3) and human lung carcinoma (A549) cells. Peptide 2 readily translocated 4 into the cytoplasms of NIH3T3 cells. However, the peptide/oligonucleotide complex was accumulated around the plasma membrane of the A549 cells.
Wada
Shun-ichi
S
Laboratory of Medicinal Chemistry, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. wada@gly.oups.ac.jp
Tanaka
Reiko
R
D016475:3T3 Cells; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D009696:Nucleic Acids / Q000008:administration & dosage*; D054848:Peptaibols; D010455:Peptides / Q000737:chemistry*; D014407:Tumor Cells, Cultured
D004337:Drug Carriers; D009696:Nucleic Acids; D054848:Peptaibols; D010455:Peptides; C106057:trichocellin