Histidine-enriched multifunctional peptide vectors with enhanced cellular uptake and endosomal escape for gene delivery

Meng, Zhao; Luan, Liang; Kang, Ziyao; Feng, Siliang; Meng, Qingbin; Liu, Keliang

doi:10.1039/c6tb02862d

Cited by 74 publications

(50 citation statements)

References 48 publications

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“…D-amino acids, such as the D-arginine residues incorporated into DAS, have been used to improve the proteolytic resistance of peptides successfully within the area of drug delivery due to their ability to avoid quick metabolism [29,34]. There have also been many reports in the literature on the use of D-amino acid substitutions to promote serum stability of targeting peptides which aligns with the results reported here [35][36][37][38][39].…”

Section: Discussionsupporting

confidence: 83%

Design, stability and efficacy of a new targeting peptide for nanoparticulate drug delivery to SH-SY5Y neuroblastoma cells

Huey

Rathbone

McCarron

et al. 2019

Journal of Drug Targeting

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In recent years, rabies virus-derived peptide (RDP) has shown promise as a specific neural cell targeting ligand, however stability of the peptide in human serum was unknown. Herein, we report the molecular modelling and design of an optimised peptide sequence based on interactions of RDP with the 7 subunit of the nicotinic acetylcholine receptor (nAChR). The new sequence, named DAS, designed around a 5-mer sequence which demonstrated optimal nAChR binding in silico, showed greatly improved stability for up to 8 hours in human serum in comparison to RDP, which degraded within 2 hours at 37 °C. In vitro analysis using SH-SY5Y neuroblastoma cells showed that DAS-conjugated nanoparticles containing the cytotoxic drug doxorubicin (DAS-Dox-NP) displayed significantly enhanced cytotoxicity compared with untargeted doxorubicin-loaded nanoparticles (Dox-NP). DAS-Dox-NP had no significant effect on non-neural cell types, confirming its neural-specific targeting properties. This is the first time that In this manuscript, we report the design and testing of an optimised peptide ligand, conjugated to a nanoparticulate delivery vehicle and specifically targeted to neural cells., has been reported. Future impact of an innovative targeting peptide ligand combining the ability to selectively identify the target and facilitate cellular internalisation could enable the successful treatment of many neural cell disorders.

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Section: Discussionsupporting

confidence: 83%

Design, stability and efficacy of a new targeting peptide for nanoparticulate drug delivery to SH-SY5Y neuroblastoma cells

Huey

Rathbone

McCarron

et al. 2019

Journal of Drug Targeting

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“…According to our previous work, when both the TAT segment and (LLHH) 3 are present in a peptide, transfection is enhanced. 32 Similarly, P-06 exhibited greater transfection efficiency compared with P-02 in the present study. Moreover, when the CPP segment was R 9 , the presence of (LLKK) 3 -H 6 contributed to enhanced transfection efficiency.…”

Section: Transfection Efficiencysupporting

confidence: 56%

The structure and configuration changes of multifunctional peptide vectors enhance gene delivery efficiency

et al. 2018

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We designed a series of peptide vectors that contain functional fragments with the goal of enhancing cellular internalization and gene transfection efficiency. The functional fragments included a cellpenetrating peptide (R 9 ), a cationic amphiphilic a-helical peptide [(LLKK) 3 -H 6 or (LLHH) 3 ], a stearyl moiety, and cysteine residues. Vectors were also synthesized with D-type amino acids to improve their proteolytic stability. The conformations, particle sizes, and zeta potentials for complexes of these peptides with pGL3 plasmid DNA were characterized by circular dichroism and dynamic light scattering.In addition, cellular uptake of the peptide/DNA complexes and gene transfection efficiency were investigated with fluorescence-activated cell sorting and confocal laser-scanning microscopy. Greater transfection efficiency was achieved with the vectors containing the R 9 segment, and the efficiency was greater than Lipo2000. In addition, the D-type C 18 -c(llkk) 3 ch 6 -r 9 had about 7 times and 5.5 times the transfection efficiency of Lipo2000 in 293T cells and NIH-3T3 cells at the N/P ratio of 6, respectively. Overall, the multifunctional peptide gene vectors containing the R 9 segment exhibited enhanced cellular internalization, a high gene transfection efficiency, and low cytotoxicity.

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“…To achieve these delivery results, we fused the CPP Human Immunodeficiency Virus (HIV)-TAT variant PTD4 ( ) [ 19 ], with the cationic amphiphilic α-helical ELD CM18 ( ) [ 13 ]. We geared this chimeric peptide with six consecutive histidine residues in the N-terminal position to improve endosomal destabilization through their proton sponge effect [ 20 , 21 ]. Importantly, the 6His-CM18-PTD4 peptide was not fused or conjugated to protein cargoes.…”

Section: Introductionmentioning

confidence: 99%

Membrane permeabilizing amphiphilic peptide delivers recombinant transcription factor and CRISPR-Cas9/Cpf1 ribonucleoproteins in hard-to-modify cells

et al. 2018

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Delivery of recombinant proteins to therapeutic cells is limited by a lack of efficient methods. This hinders the use of transcription factors or Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) ribonucleoproteins to develop cell therapies. Here, we report a soluble peptide designed for the direct delivery of proteins to mammalian cells including human stem cells, hard-to-modify primary natural killer (NK) cells, and cancer cell models. This peptide is composed of a 6x histidine-rich domain fused to the endosomolytic peptide CM18 and the cell penetrating peptide PTD4. A less than two-minute co-incubation of 6His-CM18-PTD4 peptide with spCas9 and/or asCpf1 CRISPR ribonucleoproteins achieves robust gene editing. The same procedure, co-incubating with the transcription factor HoxB4, achieves transcriptional regulation. The broad applicability and flexibility of this DNA- and chemical-free method across different cell types, particularly hard-to-transfect cells, opens the way for a direct use of proteins for biomedical research and cell therapy manufacturing.

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Histidine-enriched multifunctional peptide vectors with enhanced cellular uptake and endosomal escape for gene delivery

Abstract: Peptide vectors offer a promising gene delivery approach because of their biocompatibility and ease of functionalization.

Cited by 74 publications

References 48 publications

Design, stability and efficacy of a new targeting peptide for nanoparticulate drug delivery to SH-SY5Y neuroblastoma cells

Design, stability and efficacy of a new targeting peptide for nanoparticulate drug delivery to SH-SY5Y neuroblastoma cells

The structure and configuration changes of multifunctional peptide vectors enhance gene delivery efficiency

Membrane permeabilizing amphiphilic peptide delivers recombinant transcription factor and CRISPR-Cas9/Cpf1 ribonucleoproteins in hard-to-modify cells

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