Arginine-rich cell-penetrating peptides deliver gene into living human cells

Liu, Betty Revon; Lin, Ming-Der; Chiang, Hsin‐Ju; Lee, Han-Jung

doi:10.1016/j.gene.2012.05.053

Cited by 54 publications

(32 citation statements)

References 54 publications

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“…Furthermore, the higher pK a values of guanidines (e.g., pK a of arginine gunidinium group = 12.48) when compared with amines (e.g., pK a of lysine amino group = 10.53) would also mean that a higher proportion of guanidines would be charged at physiological pH, imparting a greater cationic character. A high concentration of guanidines can also assist with translocation across membranes [11,[15][16][17] thus underlying the fact that polyarginine functions as a cell-penetrating peptide [18][19][20]. As a result, a number of guanidine-based polymers and nanoparticles have been designed as potential drug delivery vehicles to facilitate the transport of drugs to intracellular targets [21][22][23][24].…”

Section: Guanylated Polymethacrylatesmentioning

confidence: 99%

Structure–activity relationships of guanylated antimicrobial polymethacrylates

Locock

Michl

Griesser

et al. 2014

Pure and Applied Chemistry

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Host-defense antimicrobial peptides (AMPs) are a promising lead in the search for novel antibiotics. Many of these peptides exhibit broad-spectrum antibacterial ability, low toxicity toward human cells, and little susceptibility to induction of bacterial resistance. Our research focuses on the development of synthetic polymers that are able to mimic the amphiphilic and cation-rich characteristics of AMPs. This derives bioactive polymers that retain the activity profile of AMPs while utilizing a construct that is less expensive and easier to produce and manipulate chemically. This review details structure-activity relationships (SARs) of a new class of arginine-rich, synthetic AMP mimicking polymers (SAMPs), the guanylated polymethacrylates. These are contrasted with those of amine-based polymers that are mimics of lysine-rich AMPs. The ideal composition for candidates for practical applications was identified as those containing guanidines as a cation source, having a low molecular weight and a low level of lipophilicity. This gave polymers with high potency against Gram-positive strains of bacteria (e.g., Staphylococcus epidermidis MIC = 10 μg/mL) and low toxicity towards human red blood cells ( < 4 % hemolysis at given MIC). This work emphasizes the need to rationalize observed biological activities based not purely on the global lipophilic and cationic character of polymers but rather to consider the profound effect that specific pendant functional groups may have on the potency, selectivity, and mechanisms behind the action of antimicrobial polymers.

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Section: Guanylated Polymethacrylatesmentioning

confidence: 99%

Structure–activity relationships of guanylated antimicrobial polymethacrylates

Locock

Michl

Griesser

et al. 2014

Pure and Applied Chemistry

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“…Arginine- or lysine-rich CPPs can deliver such cargoes into cells in vitro and in vivo [2,3,4]. Although the endocytic pathway has been thought to be significant [5], more than 90% of the delivered cargo become biologically inactive because of lysosomal degradation [6].…”

Section: Introductionmentioning

confidence: 99%

Glycosaminoglycan Binding and Non-Endocytic Membrane Translocation of Cell-Permeable Octaarginine Monitored by Real-Time In-Cell NMR Spectroscopy

et al. 2017

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Glycosaminoglycans (GAGs), which are covalently-linked membrane proteins at the cell surface have recently been suggested to involve in not only endocytic cellular uptake but also non-endocytic direct cell membrane translocation of arginine-rich cell-penetrating peptides (CPPs). However, in-situ comprehensive observation and the quantitative analysis of the direct membrane translocation processes are challenging, and the mechanism therefore remains still unresolved. In this work, real-time in-cell NMR spectroscopy was applied to investigate the direct membrane translocation of octaarginine (R8) into living cells. By introducing 4-trifluoromethyl-l-phenylalanine to the N terminus of R8, the non-endocytic membrane translocation of 19F-labeled R8 (19F-R8) into a human myeloid leukemia cell line was observed at 4 °C with a time resolution in the order of minutes. 19F NMR successfully detected real-time R8 translocation: the binding to anionic GAGs at the cell surface, followed by the penetration into the cell membrane, and the entry into cytosol across the membrane. The NMR concentration analysis enabled quantification of how much of R8 was staying in the respective translocation processes with time in situ. Taken together, our in-cell NMR results provide the physicochemical rationale for spontaneous penetration of CPPs in cell membranes.

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“…Muratovska and Eccles investigated the transfection efficiency of different CPPs (e.g., penetratin) conjugated to siRNA via disulfide bonds and reported that these CPP–siRNAs efficiently reduced transient and stable expression of reporter transgenes in different cell types equivalent or better than cationic liposomes. Disulfide bonds were said to increase CPP affinity for genetic material (e.g., DNA or RNA) by the ‘chelate effect’, which increases the complex stability and reduces cyto-toxicity by rapid degradation in the cytoplasmic space [46,47]. Other studies have observed that cysteine residues added onto CPPs can have a significant impact on delivery.…”

Section: Formulation Strategiesmentioning

confidence: 99%

“…In another report, arginine-rich CPPs (PR9, SR9 and HR9) were used to deliver genetic material into target cells. The researchers proposed that calcium condensed CPPs/DNA complexes into small particles and that including calcium chloride caused a significant increase in cellular internalization and gene expression (Figure 5) [46]. …”

Section: Current Applications Using the Noncovalent Strategymentioning

confidence: 99%

“…Other investigators studied the gene expression of three arginine-rich CPPs (SR9, PR9 and HR9). Researchers indicated that HR9 was superior, possibly because the histidine facilitated DNA endosomal escape [46]. Another group indicated that efficient endosomolytic peptides, such as EB1, can be applied to enhance the ability of CPP/siRNA complexes to effectively deliver siRNA across the endosomal membrane [94].…”

Section: Current Applications Using the Noncovalent Strategymentioning

confidence: 99%

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Noncovalently Associated cell-penetrating Peptides for Gene Delivery Applications

et al. 2013

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The use of various cell-penetrating peptides (CPPs) to deliver genetic material for gene therapy applications has been a topic of interest for more than 20 years. The delivery of genetic material by using CPPs can be divided into two categories: covalently bound and electrostatically bound. Complexity of the synthesis procedure can be a significant barrier to translation when using a strategy requiring covalent binding of CPPs. In contrast, electrostatically complexing CPPs with genetic material or with a viral vector is relatively simple and has been demonstrated to improve gene delivery in both in vitro and in vivo studies. This review highlights gene therapy applications of complexes formed noncovalently between CPPs and genetic material or viruses.

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Arginine-rich cell-penetrating peptides deliver gene into living human cells

Cited by 54 publications

References 54 publications

Structure–activity relationships of guanylated antimicrobial polymethacrylates

Structure–activity relationships of guanylated antimicrobial polymethacrylates

Glycosaminoglycan Binding and Non-Endocytic Membrane Translocation of Cell-Permeable Octaarginine Monitored by Real-Time In-Cell NMR Spectroscopy

Noncovalently Associated cell-penetrating Peptides for Gene Delivery Applications

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