On the Mechanism of Eukaryotic Cell Penetration by α‐ and β‐Oligoarginines – Targeting Infected Erythro­cytes

Abstract

Fluorescein-labeled α- and β-octaarginine amides were synthesized. The route, by which these oligoarginine (OA) derivatives enter cells (hepatocytes, fibroblasts, macrophages), was investigated by confocal fluorescence microscopy. Comparisons (by co-localization experiments) with compounds of known penetration modes revealed that the β-octaarginine amide also uses multiple pathways to enter cells. There was no difference between the α- and the β-OAs. Like other cell-penetrating peptides (CPPs), the β-octaarginine eventually winds up in the nucleoli of the cell nuclei (cf. Chem. Biodiversity, 2004, 1, 65). Surprisingly, there was no entry of α- or β-OA into intact and healthy human erythrocytes (which do not possess a nucleus). Blood cells infected by Plasmodium falciparum (malaria parasite) were, however, entered readily, and the OAs went all the way through a couple of membranes into the parasite. The potential of these results for delivering specific antimalarial drugs directly into the parasite is discussed.

An overview of peptide and peptoid foldamers in medicinal chemistry

“…The cross-linking led to a considerable increase in the stability of the helical structure, but nonetheless the cell-uptake of the foldamers could be increased noticeably only by the introduction of arginines [78]. The greatest advance in this field was achieved by the utilization of a-and b-arginine oligomers in the treatment of malaria caused by Plasmodium falciparum [79,80]. Whereas these oligomers do not cross the cell membrane of healthy erythrocytes, they can pass through the cell membrane of infected erythrocytes.…”

The Cell’s Nucleolus: an Emerging Target for Chemotherapeutic Intervention

“…Another CPP, fluorescein-labeled β 3-octaarginine, [77] was shown by confocal microscopy to localize to the nucleoli of erythrocytes infected with Plasmodium falciparum , however, was unable to enter intact, healthy erythrocytes. These properties could lead to the development of novel drug-conjugated CPPs that selectively deliver drugs to infected (or malignant) cells.…”

Antibacterial Activity of Enrofloxacin and Ciprofloxacin Derivatives of β‐Octaarginine

“…Still, they turned out to be useful model systems for in-vitro investigations: b-OAs with chain lengths in the range of 7 -10 residues penetrate into eukarytic cells rapidly and accumulate in the nuclei and nucleoli of mammalian skin cells [2] [22a,b,h,i] and HeLa cells [22b], and they enter hepatocytes, fibroblasts, macrophages and -infected onlyerythrocytes [2]. Not just the architecturally rather simple cell walls of eukaryotes but also the highly sophisticated multilayer cell walls of prokaryotic organisms (Grampositive and Gram-negative [22c]) and of parasites (unicellular eukaryotes) [2] are passed by b-OAs. No antimicrobial (in a standard collection of microorganisms [22b,d]) or cytotoxic activities of b-OAs (for skin cells and erythrocytes [22b,d]) have been detected.…”

“…In conclusion, the b-OAs have properties that qualitatively resemble those of a-OAs, especially when the latter consist of d-residues. On the other hand, many interesting and partially intriguing properties of polycationic CPPs have been unveiled in the course of investigations carried out with b-OAs [2] [13] [19] [22].…”