Truncated peptides from melittin and its analog with high lytic activity at endosomal pH enhance branched polyethylenimine‐mediated gene transfection

Yang, Tan; Chen, Chong; Wang, Yingli; Lin, Song; Wang, Yang; Li, Su-Bo; Jin, Xiao-Pan; Gao, Hongwei; Du, Fu‐Sheng; Gao, Feng; Ji, Shou‐Ping

doi:10.1002/jgm.2609

Cited by 25 publications

(22 citation statements)

References 29 publications

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“…We will also further improve these materials by incorporating different melittin analogs that were reported to mediate efficient transfection without compromised cell viability. [30, 32, 37, 46, 47]…”

Section: Discussionmentioning

confidence: 99%

Melittin-grafted HPMA-oligolysine based copolymers for gene delivery

et al. 2013

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Non-viral gene delivery systems capable of transfecting cells in the brain are critical in realizing the potential impact of nucleic acid therapeutics for diseases of the central nervous system. In this study, the membrane-lytic peptide melittin was incorporated into block copolymers synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. The first block, designed for melittin conjugation, was composed of N-(2-hydroxypropyl)methacrylamide (HPMA) and pyridyl disulfide methacrylamide (PDSMA) and the second block, designed for DNA binding, was composed of oligo-L-lysine (K10) and HPMA. Melittin modified with cysteine at the C-terminus was conjugated to the polymers through the pyridyl disulfide pendant groups via disulfide exchange. The resulting pHgMelbHK10 copolymers are more membrane-lytic than melittin-free control polymers, and efficiently condensed plasmid DNA into salt-stable particles (~ 100–200 nm). The melittin-modified polymers transfected both HeLa and neuron-like PC-12 cells more efficiently than melittin-free polymers although toxicity associated with the melittin peptide was observed. Optimized formulations containing the luciferase reporter gene were delivered to mouse brain by intraventricular brain injections. Melittin-containing polyplexes produced about 35-fold higher luciferase activity in the brain compared to polyplexes without melittin. Thus, the melittin-containing block copolymers described in this work are promising materials for gene delivery to the brain.

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Section: Discussionmentioning

confidence: 99%

Melittin-grafted HPMA-oligolysine based copolymers for gene delivery

et al. 2013

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“…This could pose difficulties given melittin's initial electrostatic attraction to negatively charged lipid components. In fact, detailed biophysical studies have revealed that melittin's ability to bind to and disrupt model membranes actually decreases as pH decreases (Tan et al 2012). Nonetheless, melittin has been shown to be capable of altering endosomal membrane integrity after cellular uptake under sub-toxic concentrations, suggesting that melittin does bind to and alter endosomal membranes despite the acidic environment (Rozema et al 2003).…”

Section: Melittin As a Basis For Endosomal Escapementioning

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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“…As we show below, endosomal release can be very inefficient (19,25,29,30) and can effectively prevent the delivery of some endocytosed cargos to the cytosol. Given this roadblock to delivery, various approaches based on physical or osmotic lysis of endosomes have been tested to increase the efficiency of endosomal release postuptake (22,29,(31)(32)(33)(34). Still, despite significant efforts over the last two decades, the highly cationic cell-penetrating peptides have yet to achieve their potential as delivery vehicles in the laboratory or in the clinic.…”

mentioning

confidence: 99%

Direct Cytosolic Delivery of Polar Cargo to Cells by Spontaneous Membrane-translocating Peptides

He¹,

Kauffman²,

Fuselier³

et al. 2013

Journal of Biological Chemistry

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Background: Spontaneous membrane-translocating peptides were discovered by screening in synthetic lipid vesicles. Results: The translocating peptides carry membrane-impermeant cargos directly across cell membranes and drive systemic biodistribution in small animals. Conclusion: These peptides constitute a new class of delivery vehicle for membrane-impermeant cargos. Significance: Spontaneous membrane-translocating peptides could expand the universe of useful drugs.

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Truncated peptides from melittin and its analog with high lytic activity at endosomal pH enhance branched polyethylenimine‐mediated gene transfection

Abstract: The results obtained in the present study indicate that the truncated peptides with higher endosomal disrupting activity were better enhancers for increasing transfection efficiency.

Cited by 25 publications

References 29 publications

Melittin-grafted HPMA-oligolysine based copolymers for gene delivery

Melittin-grafted HPMA-oligolysine based copolymers for gene delivery

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

Direct Cytosolic Delivery of Polar Cargo to Cells by Spontaneous Membrane-translocating Peptides

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