Arginine-rich peptides and their internalization mechanisms

Futaki, Shiroh; Nakase, Ikuhiko; Tadokoro, Akiko; Takeuchi, Toshihide; Jones, Arwyn Tomos

doi:10.1042/bst0350784

Cited by 208 publications

(171 citation statements)

References 31 publications

(58 reference statements)

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“…On the basis of these results, we suggest that hLF1-11 comprises two regions that are important for its ability to inhibit the enzymatic activity of MPO; that is, the arginines that bind to the crevice of the active site by electrostatic interactions and the cysteine that interferes with ROS. In addition, the arginines may mediate binding to and entry into cells (26,27). Together, our results with human monocytes and (immobilized) MPO indicate that hLF1-11 inhibits the enzymatic activities of both intracellular and extracellular MPO.…”

Section: Discussionsupporting

confidence: 52%

The Human Lactoferrin-Derived Peptide hLF1-11 Exerts Immunomodulatory Effects by Specific Inhibition of Myeloperoxidase Activity

Does

Hensbergen

Bogaards

et al. 2012

The Journal of Immunology

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Because of their ability to eliminate pathogens and to modulate various host immune responses, antimicrobial peptides are considered as candidate agents to fight infections by (antibiotic-resistant) pathogens. We recently reported that hLF1-11 (GRRRRSVQWCA), an antimicrobial peptide derived from the N terminus of human lactoferrin, displays diverse modulatory activities on monocytes, thereby enhancing their actions in innate immune responses. The aim of this study was to identify the cellular target of hLF1-11 that mediates these effects. Results revealed that hLF1-11 binds and subsequently penetrates human monocytes, after which it inhibits the enzymatic activities of myeloperoxidase (MPO). Moreover, a chemical inhibitor of MPO (aminobenzoic acid hydrazide) mimicked the effects of hLF1-11 on the inflammatory response by monocytes and on monocyte–macrophage differentiation. Computer-assisted molecular modeling predicted that hLF1-11 can bind to the edge of and within the crevice of the active site of MPO. Experiments with a set of hLF1-11 peptides with amino acid substitutions identified the stretch of arginines and the cysteine at position 10 as pivotal in these immunomodulatory properties of hLF1-11. We conclude that hLF1-11 may exert its modulatory effects on human monocytes by specific inhibition of MPO activity.

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Section: Discussionsupporting

confidence: 52%

The Human Lactoferrin-Derived Peptide hLF1-11 Exerts Immunomodulatory Effects by Specific Inhibition of Myeloperoxidase Activity

Does

Hensbergen

Bogaards

et al. 2012

The Journal of Immunology

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“…The strong and universal translocation of arginine-rich cellpenetrating peptides in multiple cell types has also triggered speculation on the involvement of some common molecules like cell surface GAGs in the process of cellular entry, although it is still debatable whether membrane translocation and endocytotic uptake are both involved (14). Cell-penetrating peptides like naturally occurring protein transduction domains, e.g.…”

mentioning

confidence: 99%

Exogenous and Cell Surface Glycosaminoglycans Alter DNA Delivery Efficiency of Arginine and Lysine Homopeptides in Distinctly Different Ways

Naik¹,

Chandra

Mann³

et al. 2011

Journal of Biological Chemistry

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Glycosaminoglycans (GAGs) expressed ubiquitously on the cell surface are known to interact with a variety of ligands to mediate different cellular processes. However, their role in the internalization of cationic gene delivery vectors such as liposomes, polymers, and peptides is still ambiguous and seems to be controlled by multiple factors. In this report, taking peptides as model systems, we show that peptide chemistry is one of the key factors that determine the dependence on cell surface glycosaminoglycans for cellular internalization and gene delivery. Arginine peptides and their complexes with plasmid DNA show efficient uptake and functional gene transfer independent of the cell surface GAGs. On the other hand, lysine peptides and complexes primarily enter through a GAG-dependent pathway. The peptide-DNA complexes also show differential interaction with soluble GAGs. In the presence of exogenous GAGs under certain conditions, arginine peptide-DNA complexes show increased transfection efficiency that is not observed with lysine. This is attributed to a change in the complex nature that ensures better protection of the compacted DNA in the case of arginine complexes, whereas the lysine complexes get destabilized under these conditions. The presence of a GAG coating also ensures better cell association of arginine complexes, resulting in increased uptake. Our results indicate that the role of both the cell surface and exogenous glycosaminoglycans in gene delivery is controlled by the nature of the peptide and its complex with DNA.

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“…However, with short incubation times, only TATp-L significantly penetrate DC since TATp readily binds to cell surface proteoglycans and triggers receptor-mediated endocytosis (macropinocytosis). 48 With sufficiently longer incubation, both formulations can be …”

Section: Discussionmentioning

confidence: 99%

In vitro transfection of bone marrow-derived dendritic cells with TATp-liposomes

Pappalardo¹,

Langellotti²,

Giacomo³

et al. 2014

IJN

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Dendritic cells (DC) are antigen-presenting cells uniquely capable of priming naïve T cells and cross-presenting antigens, and they determine the type of immune response elicited against an antigen. TAT peptide (TATp), is an amphipathic, arginine-rich, cationic peptide that promotes penetration and translocation of various molecules and nanoparticles into cells. TATp-liposomes (TATp-L) used for DC transfection were prepared using TATp derivatized with a lipid-terminated polymer capable of anchoring in the liposomal membrane. Here, we show that the addition of TATp to DNA-loaded liposomes increased the uptake of DNA in DC. DNA-loaded TATp-L increased the in vitro transfection efficiency in DC cultures as evidenced by a higher expression of the enhanced green fluorescent protein and bovine herpes virus type 1 glycoprotein D (gD). The de novo synthesized gD protein was immunologically stimulating when transfections were performed with TATp-L, as indicated by the secretion of interleukin 6.

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Arginine-rich peptides and their internalization mechanisms

Cited by 208 publications

References 31 publications

The Human Lactoferrin-Derived Peptide hLF1-11 Exerts Immunomodulatory Effects by Specific Inhibition of Myeloperoxidase Activity

The Human Lactoferrin-Derived Peptide hLF1-11 Exerts Immunomodulatory Effects by Specific Inhibition of Myeloperoxidase Activity

Exogenous and Cell Surface Glycosaminoglycans Alter DNA Delivery Efficiency of Arginine and Lysine Homopeptides in Distinctly Different Ways

In vitro transfection of bone marrow-derived dendritic cells with TATp-liposomes

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