Structure-activity relationship study on a simple cationic peptide motif for cellular delivery of antisense peptide nucleic acid.
Improving cellular uptake and biodistribution remains one of the major obstacles for a successful and broad application of peptide nucleic acids (PNAs) as antisense therapeutics. Recently, we reported the identification and functional characterization of an antisense PNA, which redirects splicing of murine CD40 pre-mRNA. In this context, it was discovered that a simple octa(l-lysine) peptide covalently linked to the PNA is capable of promoting free uptake of the conjugate into BCL1 cells as well as primary murine macrophages. On the basis of this peptide motif, the present study aimed at identifying the structural features, which define effective peptide carriers for cellular delivery of PNA. While the structure-activity relationship study revealed some clear correlations, only a few modifications actually led to an overall improvement as compared to the parent octa(l-lysine) conjugate. In a preliminary PK/tissue distribution study in healthy mice, the parent conjugate exhibited relatively broad tissue distribution and only modest elimination via excretion within the time frame of the study.
Albertshofer
Klaus
K
Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc., 1891 Rutherford Road, Carlsbad, CA 92008, USA.
Siwkowski
Andrew M
AM
Wancewicz
Edward V
EV
Esau
Christine C
CC
Watanabe
Tanya
T
Nishihara
Kenji C
KC
Kinberger
Garth A
GA
Malik
Leila
L
Eldrup
Anne B
AB
Manoharan
Muthiah
M
Geary
Richard S
RS
Monia
Brett P
BP
Swayze
Eric E
EE
Griffey
Richard H
RH
Bennett
C Frank
CF
Maier
Martin A
MA
D000818:Animals; D001120:Arginine / Q000737:chemistry*; D002412:Cations; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D008239:Lysine / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D020135:Peptide Nucleic Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D002412:Cations; D004337:Drug Carriers; D009842:Oligopeptides; D020135:Peptide Nucleic Acids; D001120:Arginine; D008239:Lysine