title: Delivery of 2-5A cargo into living cells using the Tat cell penetrating peptide: 2-5A-tat.
abstract: 2',5'-Oligoadenylate tetramer (2-5A) has been chemically conjugated to short HIV-1 Tat peptides to provide 2-5A-tat chimeras. Two different convergent synthetic approaches have been employed to provide such 2-5A-tat bioconjugates. One involved generation of a bioconjugate through reaction of a cysteine terminated Tat peptide with a alpha-chloroacetyl derivative of 2-5A. The second synthetic strategy was based upon a cycloaddition reaction of an azide derivative of 2-5A with a Tat peptide bearing an alkyne function. Either bioconjugate of 2-5A-tat was able to activate human RNase L. The union of 2-5A and Tat peptide provided an RNase L-active chimeric nucleopeptide with the ability to be taken up by cells by virtue of the Tat peptide and to activate RNase L in intact cells. This strategy provides a valuable vehicle for the entry of the charged 2-5A molecule into cells and may provide a means for targeted destruction of HIV RNA in vivo.
authors.affiliation: Department of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, AZ 86011-5698, USA.
authors.forename: Longhu
authors.initials: L
authors.lastname: Zhou
authors.forename: Chandar S
authors.initials: CS
authors.lastname: Thakur
authors.forename: Ross J
authors.initials: RJ
authors.lastname: Molinaro
authors.forename: Jayashree M
authors.initials: JM
authors.lastname: Paranjape
authors.forename: Rieuwert
authors.initials: R
authors.lastname: Hoppes
authors.forename: Kuan-Teh
authors.initials: KT
authors.lastname: Jeang
authors.forename: Robert H
authors.initials: RH
authors.lastname: Silverman
authors.forename: Paul F
authors.initials: PF
authors.lastname: Torrence
mesh_terms: D000227:Adenine Nucleotides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000480:Alkynes; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001386:Azides; D002463:Cell Membrane Permeability / Q000187:drug effects; D016503:Drug Delivery Systems; D004722:Endoribonucleases / Q000187:drug effects; D015696:Gene Products, tat / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D009843:Oligoribonucleotides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000227:Adenine Nucleotides; D000480:Alkynes; D019380:Anti-HIV Agents; D001386:Azides; D015696:Gene Products, tat; D009843:Oligoribonucleotides; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C023505:2',5'-oligoadenylate; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease