New generation of efficient peptide-based vectors, NickFects, for the delivery of nucleic acids

Arukuusk, Piret; Pärnaste, Ly; Oskolkov, Nikita; Copolovici, Dana; Margus, Helerin; Padari, Kärt; Möll, Kaidi; Maslovskaja, Julia; Tegova, Radi; Kivi, Gaily; Tover, Andres; Pooga, Margus; Ustav, Mart; Langel, Ülo

doi:10.1016/j.bbamem.2013.01.011

Cited by 79 publications

(59 citation statements)

References 35 publications

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“…The calculation results are comparable to the experimentally determined efficiency of the different peptides of delivery of siRNA into cells, which are shown in Table 3 [25, 26]. There is the same trend between the downregulation experiments and the binding scores.…”

Section: Resultssupporting

confidence: 77%

Peptide-Ligand Binding Modeling of siRNA with Cell-Penetrating Peptides

García-Sosa

Tulp

Langel

et al. 2014

BioMed Research International

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The binding affinity of a series of cell-penetrating peptides (CPP) was modeled through docking and making use of the number of intermolecular hydrogen bonds, lipophilic contacts, and the number of sp3 molecular orbital hybridization carbons. The new ranking of the peptides is consistent with the experimentally determined efficiency in the downregulation of luciferase activity, which includes the peptides' ability to bind and deliver the siRNA into the cell. The predicted structures of the complexes of peptides to siRNA were stable throughout 10 ns long, explicit water molecular dynamics simulations. The stability and binding affinity of peptide-siRNA complexes was related to the sidechains and modifications of the CPPs, with the stearyl and quinoline groups improving affinity and stability. The reranking of the peptides docked to siRNA, together with explicit water molecular dynamics simulations, appears to be well suited to describe and predict the interaction of CPPs with siRNA.

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Section: Resultssupporting

confidence: 77%

Peptide-Ligand Binding Modeling of siRNA with Cell-Penetrating Peptides

García-Sosa

Tulp

Langel

et al. 2014

BioMed Research International

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“…The main goal for all CPPs in cancer cell studies is to deliver anticancer agents into cytoplasm/nucleus without causing damage to the cell membrane. Recently, siRNA [41], plasmid DNA [34], PNA [42] or PMO (Morpholino oligomers) [43] agents have been intensively studied in order to trigger specific cellular responses via up or down regulation of gene expression. Moreover, CPPs were used for the induction of direct cellular death by the introduction of doxorubicin [44] or anti-cancer drug paclitaxel [45] into the cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Protein and siRNA delivery by transportan and transportan 10 into colorectal cancer cell lines

Wierzbicki

Kogut-Wierzbicka

Ruczyński

et al. 2015

Folia Histochem Cytobiol.

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Introduction. Cell penetrating peptides (CPPs) have the ability to translocate through cell membranes with high efficiency and therefore can introduce biological agents with pharmaceutical properties into the cell. Transportan (TP) and its shorter analog transportan 10 (TP10) are among the best studied CPPs, however, their effects on viability of and cargo introduction into colorectal cancer (CRC) cells have yet not been investigated. The aim of our study was to evaluate the cytotoxic effects of TP and TP10 on representative CRC lines and the efficiency of protein (streptavidin) and siRNA cargo delivery by TP-biotinylated derivatives (TP-biot). Material and methods. HT29 (early stage CRC model) and HCT116 (metastatic CRC model) cell lines were incubated with TP, TP10, TP-biot1, TP-biot13 and TP10-biot1. The effects of studied CPPs on cell viability and cell cycle were assessed by MTT and annexin V assays. The uptake of streptavidin-FITC complex into cells was determined by flow cytometry and fluorescence microscopy, with the inhibition of cellular vesicle trafficking by brefeldin A. The efficiency of siRNA for SASH1 gene delivery was measured by quantitative PCR (qPCR). Results. Since up to 10 µM concentrations of each CPP showed no significant cytotoxic effect, the concentrations of 0.5-5 µM were used for further analyses. Within this concentration range none of the studied CPPs affected cell viability and cell cycle. The efficient and endocytosis-independent introduction of streptavidin-FITC complex into cells was observed for TP10-biot1 and TP-biot1 with the cytoplasmic location of the fluorescent cargo; decreased SASH1 mRNA level was noticed with the use of siRNA and analyzed CPPs. Conclusions. We conclude that TP, TP10 and their biotinylated derivatives can be used as efficient delivery vehicles of small and large cargoes into CRC cells.

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“…Modifications made to TP10 include stearylation, replacement of lysines by ornithines, addition of trifluoromethylquinolone side chains, chemical modification with UV light responsive side chains and oligomerization (Regberg et al 2014). These modifications have resulted in a range of “PepFect” and “NickFect” peptides, which deliver siRNA, splice correcting oligos, and even plasmid DNA through a mechanism that involves Scavenger Receptor A mediated endocytosis (Hassane et al 2011, Ezzat et al 2012, Arukuusk et al 2013). …”

Section: Cationic Peptides For Sirna Transfectionmentioning

confidence: 99%

A role for peptides in overcoming endosomal entrapment in siRNA delivery — A focus on melittin

Hou

Pan

Schlesinger

et al. 2015

Biotechnology Advances

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siRNA has the possibility to revolutionize medicine by enabling highly specific and efficient silencing of proteins involved in disease pathogenesis. Despite nearly 20 years of research dedicated to translating siRNA from a research tool into a clinically relevant therapeutic, minimal success has been had to date. Access to RNA interference machinery located in the cytoplasm is often overlooked, but must be considered when designing the next generation of siRNA delivery strategies. Peptide transduction domains (PTD) have demonstrated moderate siRNA transfection, which is primarily limited by endosomal entrapment. Strategies aimed at overcoming endosomal entrapment associated with peptide vectors are reviewed here, including osmotic methods, lipid conjugation, and fusogenic peptides. As an alternative to traditional PTD, the hemolytic peptide melittin exhibits the native capacity for endosomal disruption but causes cytotoxicity. However, appropriate packaging and protection of melittin with activation and release in the endosomal compartment has allowed melittin-based strategies to demonstrate both in vitro and in vivo safety and efficacy. These data suggest that melittin's membrane disruptive properties can enable safe and effective endosomolysis, building a case for melittin as a key component in a new generation of siRNA therapeutics.

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New generation of efficient peptide-based vectors, NickFects, for the delivery of nucleic acids

Cited by 79 publications

References 35 publications

Peptide-Ligand Binding Modeling of siRNA with Cell-Penetrating Peptides

Peptide-Ligand Binding Modeling of siRNA with Cell-Penetrating Peptides

Protein and siRNA delivery by transportan and transportan 10 into colorectal cancer cell lines

A role for peptides in overcoming endosomal entrapment in siRNA delivery — A focus on melittin

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