Functional Delivery of siRNA by Disulfide-Constrained Cyclic Amphipathic Peptides

Welch, Jade J.; Swanekamp, Ria J.; King, C. P.; Dean, David A.; Nilsson, Bradley L.

doi:10.1021/acsmedchemlett.6b00031

Cited by 28 publications

(49 citation statements)

References 42 publications

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“…Moreover, a novel fusion protein containing the tombusviral p19 protein linked to the 'Tat' peptide (RKKRRQRRRR) could efficiently deliver siRNAs into the cytoplasm of human hepatoma cells eliciting potent gene knockdown activity without cytotoxicity [203]. Disulfide-constrained cyclic amphipathic peptides increased siRNA penetration into the cells through the formation of noncovalent peptide/siRNA complexes [204]. Recently, amphipathic peptides were developed to self-assemble with siRNAs as peptide-based nanoparticles and to transfect them into cells.…”

Section: Nucleic Acid Deliverymentioning

confidence: 99%

Cell penetrating peptides: the potent multi-cargo intracellular carriers

Kardani

Milani

Shabani

et al. 2019

Expert Opinion on Drug Delivery

143

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Introduction: Cell penetrating peptides (CPPs) known as protein translocation domains (PTD), membrane translocating sequences (MTS), or Trojan peptides (TP) are able to cross biological membranes without clear toxicity using different mechanisms, and facilitate the intracellular delivery of a variety of bioactive cargos. CPPs could overcome some limitations of drug delivery and combat resistant strains against a broad range of diseases. Despite delivery of different therapeutic molecules by CPPs, they lack cell specificity and have a short duration of action. These limitations led to design of combined cargo delivery systems and subsequently improvement of their clinical applications. Areas covered: This review covers all our studies and other researchers in different aspects of CPPs such as classification, uptake mechanisms, and biomedical applications. Expert opinion: Due to low cytotoxicity of CPPs as compared to other carriers and final degradation to amino acids, they are suitable for preclinical and clinical studies. Generally, the efficiency of CPPs was suitable to penetrate the cell membrane and deliver different cargos to specific intracellular sites. However, no CPP-based therapeutic approach has approved by FDA, yet; because there are some disadvantages for CPPs including short half-life in blood, and nonspecific CPP-mediated delivery to normal tissue. Thus, some methods were used to develop the functions of CPPs in vitro and in vivo including the augmentation of cell specificity by activatable CPPs, specific transport into cell organelles by insertion of corresponding localization sequences, incorporation of CPPs into multifunctional dendrimeric or liposomal nanocarriers to improve selectivity and efficiency especially in tumor cells.

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Section: Nucleic Acid Deliverymentioning

confidence: 99%

Cell penetrating peptides: the potent multi-cargo intracellular carriers

Kardani

Milani

Shabani

et al. 2019

Expert Opinion on Drug Delivery

143

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“…The development of biomaterials derived from self‐assembled peptides is of great current interest due to biomedical applications including controlled release drug delivery, vaccine development, tissue engineering, and wound healing . Amphipathic peptides that consist of alternating hydrophobic and hydrophilic amino acids are a privileged class of peptide that readily self‐assembles into β‐sheet bilayer nanoribbons that share the basic characteristics of cross‐β amyloid assemblies (Figure ) .…”

Section: Introductionmentioning

confidence: 99%

Balancing hydrophobicity and sequence pattern to influence self‐assembly of amphipathic peptides

2018

Self Cite

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Amphipathic peptides with alternating polar and nonpolar amino acid sequences efficiently selfassemble into functional b-sheet fibrils as long as the nonpolar residues have sufficient hydrophobicity. For example, the Ac-(FKFE) 2 -NH 2 peptide rapidly self-assembles into b-sheet bilayer nanoribbons, while Ac-(AKAE) 2 -NH 2 fails to self-assemble under similar conditions due to the significantly reduced hydrophobicity and b-sheet propensity of Ala relative to Phe. Herein, we systematically explore the effect of substituting only two of the four Ala residues at various positions in the Ac-(AKAE) 2 -NH 2 peptide with amino acids of increasing hydrophobicity, b-sheet potential, and surface area (including Phe, 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), cyclohexylalanine (Cha), and pentafluorophenylalanine (F 5 -Phe)) on the self-assembly propensity of the resulting sequences. It was found that double Phe variants, regardless of the position of substitution, failed to self-assemble under the conditions used in this study. In contrast, all double 1-Nal and 2-Nal variants readily self-assembled, albeit at differing rates depending on the substitution patterns. To determine whether this was due to hydrophobicity or side chain surface area, we also prepared double Cha and F 5 -Phe variant peptides (both side chain groups are more hydrophobic than Phe). Each of these variants also underwent effective self-assembly, with the aromatic F 5 -Phe peptides doing so with greater efficiency. These findings provide insight into the role of amino acid hydrophobicity and sequence pattern on self-assembly proclivity of amphipathic peptides and on how targeted substitutions of nonpolar residues in these sequences can be exploited to tune the characteristics of the resulting self-assembled materials.hydrophobicity, peptide, self-assembly | I N TR ODU C TI ONThe development of biomaterials derived from self-assembled peptides is of great current interest due to biomedical applications including controlled release drug delivery, vaccine development, tissue engineering, and wound healing. Amphipathic peptides that consist of alternating hydrophobic and hydrophilic amino acids are a privileged class of peptide that readily self-assembles into b-sheet bilayer nanoribbons that share the basic characteristics of cross-b amyloid assemblies (Figure 1). [23][24][25][26][27][28][29][30] These bilayer nanoribbons effectively sequester all hydrophobic functionality to the bilayer interior, leaving hydrophilic groups exposed to solvent on the exterior face. [24,[31][32][33][34] As a result, these nanoribbons maintain high solubility in aqueous solvents, making them ideal materials for biological applications. Because of the high utility of this class of amphipathic peptide, they have been widely adopted as models to study the fundamental physicochemical basis of peptide self-assembly processes in order to facilitate the rational design of next-generation materials derived from self-assembled b-sheet peptides.[ [35][36][37][38][39]...

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“…Self-assembly of cyclic peptides towards nanotube formation using D-amino acids was first developed by Ghadiri et al [30,31]. Recently, cyclic peptides L-AcC(FKFE)2CG-NH2, D-Ac-C(FKFE)2CG-NH2, L-AcC(WR)4CG-NH2 and RGD10-10R were reported for siRNA delivery and significant gene knockdown was observed in both in vitro and in vivo [32,33]. However, clinical implementation of these delivery systems is not successful yet.…”

Section: Introductionmentioning

confidence: 99%

Cyclic peptide-based nanostructures as efficient siRNA carriers

Panigrahi

Singh

Mishra

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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RNA interference shows a great strategy for biological studies; however, delivering of small interfering RNA (siRNA) remains challenging. Although several delivery vehicles, including cell-penetrating peptides, have been developed, their implementation is often restricted because of their endosomal entrapment. Herein, we report the formation of self-assembled nanostructures from rationally designed cyclic peptides and explore them for efficient delivery of functional biomacromolecules such as siRNA into mammalian cells. The newly obtained soft materials make stable complexes with siRNAs, thereby increasing their stability and deliver fluorescent labelled siRNA inside the cells as evident from confocal microscopy analysis. Flow cytometry analysis reveals that significant uptake of FAM-siRNA occurs in the presence of peptide nanostructures compared with siRNA alone. Peptide nanostructure-mediated delivery of very low concentration of siRNA causes significant knockdown of the target gene as observed at protein level by Western blot analysis, which is comparable to lipofectamine, commercially available transfection agent.

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Functional Delivery of siRNA by Disulfide-Constrained Cyclic Amphipathic Peptides

Cited by 28 publications

References 42 publications

Cell penetrating peptides: the potent multi-cargo intracellular carriers

Cell penetrating peptides: the potent multi-cargo intracellular carriers

Balancing hydrophobicity and sequence pattern to influence self‐assembly of amphipathic peptides

Cyclic peptide-based nanostructures as efficient siRNA carriers

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