The effect of preorganized versus undefined charge display on the cellular uptake of cationic cell-penetrating peptides (CPPs) was investigated by comparing conformationally well-defined guanidinylated oligoprolines with flexible oligoarginines. Flow cytometry and confocal microscopy studies with different cancer cell lines (HeLa, MCF-7, and HT-29) showed that preorganization of cationic charges in lateral distances of ≈9 Å enhanced the cellular uptake of CPPs. Binding affinity measurements revealed tighter binding of analogues of cell-surface glycans to the guanidinylated octaproline with localized charges compared to flexible octaarginine, a finding that was further correlated to the cellular uptake by studies with CHO cells deficient in glycans on the outer plasma membrane.

The effect of preorganized versus undefined charge displayo nt he cellular uptake of cationic cell-penetrating peptides (CPPs) was investigated by comparing conformationally well-defined guanidinylated oligoprolines with flexible oligoarginines.F low cytometry and confocal microscopy studies with different cancer cell lines (HeLa, showed that preorganization of cationic charges in lateral distances of % 9 enhanced the cellular uptake of CPPs.Binding affinity measurements revealed tighter binding of analogues of cell-surface glycans to the guanidinylated octaproline with localized charges compared to flexible octaarginine,afinding that was further correlated to the cellular uptake by studies with CHO cells deficient in glycans on the outer plasma membrane.

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