jm050490b_si_001.pdf (121.05 kB)
Structure−Activity Relationship Study on a Simple Cationic Peptide Motif for Cellular Delivery of Antisense Peptide Nucleic Acid
journal contribution
posted on 2005-10-20, 00:00 authored by Klaus Albertshofer, Andrew M. Siwkowski, Edward V. Wancewicz, Christine C. Esau, Tanya Watanabe, Kenji C. Nishihara, Garth A. Kinberger, Leila Malik, Anne B. Eldrup, Muthiah Manoharan, Richard S. Geary, Brett P. Monia, Eric E. Swayze, Richard H. Griffey, C. Frank Bennett, Martin A. MaierImproving 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.