Effect of Preorganized Charge‐Display on the Cell‐Penetrating Properties of Cationic Peptides

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 di...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2017-01, Vol.56 (1), p.122-126
Main Authors: Nagel, Yvonne A., Raschle, Philipp S., Wennemers, Helma
Format: Article
Language:English
Subjects:
Animals
Anticoagulants
arginine
Binding
Cancer
Cationic peptides
Cations
Cations - chemistry
Cations - pharmacokinetics
Cell Membrane Permeability
Cell surface
Cell-Penetrating Peptides - chemistry
Cell-Penetrating Peptides - pharmacokinetics
cellular uptake
CHO Cells
Confocal microscopy
Cricetulus
Cytometry
Flow cytometry
HeLa Cells
heparin
HT29 Cells
Humans
MCF-7 Cells
Microscopy
Oligopeptides - chemistry
Oligopeptides - pharmacokinetics
oligoproline
Peptides
Polysaccharides
Proline - analogs & derivatives
Proline - pharmacokinetics
Static Electricity
Tumor cell lines
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Summary: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. Matching charges: Cationic oligoprolines with charges at lateral distances of 9 Å penetrate into cancer cells at submicromolar concentrations. The cellular uptake correlates with binding affinity to the cell‐surface glycan analogue heparin with comparable distances between anionic sulfate moieties.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201607649