| Abstract
| - Improving cellular uptake and biodistribution remains one of the major obstacles for a successfuland broad application of peptide nucleic acids (PNAs) as antisense therapeutics. Recently, wereported the identification and functional characterization of an antisense PNA, which redirectssplicing 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 conjugateinto 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 peptidecarriers for cellular delivery of PNA. While the structure−activity relationship study revealedsome clear correlations, only a few modifications actually led to an overall improvement ascompared to the parent octa(l-lysine) conjugate. In a preliminary PK/tissue distribution studyin healthy mice, the parent conjugate exhibited relatively broad tissue distribution and onlymodest elimination via excretion within the time frame of the study.
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