Delivery of steric block morpholino oligomers by (R-X-R)(4) peptides: structure–activity studies

Abes, Rachida; Moulton, Hong M.; Clair, Philippe; Yang, Sung-Tae; Abes, Said; Melikov, Kamran; Prevot, Paul; Youngblood, Derek S.; Iversen, Patrick L.; Chernomordik, Leonid V.; Lebleu, Bernard

We had no clear explanation for the improved efficiency of (R-Ahx-R) 4 -PMO and (R-Ahx-R) 4 -PNA conjugates as compared to Tat or (Arg) n steric block ON constructs. Increased cellular uptake could not be the answer since, on the contrary, (R-Ahx-R) 4 -PMO conjugates were taken up less efficiently than Tat-PMO and (Arg) n -PMO conjugates in our model system (3) . Differences could originate from a different mechanism of cellular uptake with (R-Ahx-R) 4 -PMO conjugates taking profit of a more favorable route than the other CPP conjugates. Again available data did not support this hypothesis since all three conjugates were taken up by an energy-dependent pathway involving binding to cell surface proteoglycans. Along the same lines, we recently established that blocking energy-dependent processes through incubation of cells at low temperature or through ATP depletion decreased splicing correction by (R-Ahx-R) 4 -PMO conjugates and by Tat-PMO or (Arg) n -PMO ones to the same extent (10) .