Peptide–Peptide Nucleic Acid Conjugates for Modulation of Gene Expression

Fabani, Martin M.; Ivanova, Gabriela D.; Gait, Michael J.

doi:10.1039/9781847558275-00080

Cited by 6 publications

(6 citation statements)

References 99 publications

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“…Covalent strategies have been mainly reported for the delivery of DNA mimic molecules or steric block oligonucleotides, including PNA (Koppelhus et al. , 2002; Fabani et al. , 2008), phosphorodiamidate morpholino‐oligomer (PMO) (Abes et al.…”

Section: Cell‐penetrating Peptide Familiesmentioning

confidence: 99%

“…According to the stability and efficiency of the cargo, several parameters need to be considered including the type of linkage chemistry, the nature of the spacer ( Gait, 2003 ; Zatsepin et al , 2005 ). Covalent strategies have been mainly reported for the delivery of DNA mimic molecules or steric block oligonucleotides, including PNA ( Koppelhus et al , 2002 ; Fabani et al , 2008 ), phosphorodiamidate morpholino-oligomer (PMO) ( Abes et al , 2006 ; Lebleu et al , 2008 ; Moulton and Moulton, 2008 ), peptide and protein ( Snyder and Dowdy, 2005 ). Conjugation methods offer several advantages for in vivo applications including rationalization, reproducibility of the procedure, together with the control of the stoechiometry of the CPP-cargo.…”

Section: Cell-penetrating Peptide Familiesmentioning

confidence: 99%

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Twenty years of cell‐penetrating peptides: from molecular mechanisms to therapeutics

Heitz

Morris

Divita

2009

British J Pharmacology

768

707

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The recent discovery of new potent therapeutic molecules that do not reach the clinic due to poor delivery and low bioavailability have made of delivery a key stone in therapeutic development. Several technologies have been designed to improve cellular uptake of therapeutic molecules, including cell-penetrating peptides (CPPs). CPPs were first discovered based on the potency of several proteins to enter cells. Numerous CPPs have been described so far, which can be grouped into two major classes, the first requiring chemical linkage with the drug for cellular internalization and the second involving formation of stable, non-covalent complexes with drugs. Nowadays, CPPs constitute very promising tools for non-invasive cellular import of cargo and have been successfully applied for in vitro and in vivo delivery of therapeutic molecules varying from small chemical molecule, nucleic acids, proteins, peptides, liposomes and particles. This review will focus on the structure/function and cellular uptake mechanism of CPPs in the general context of drug delivery. We will also highlight the application of peptide carriers for the delivery of therapeutic molecules and provide an update of their clinical evaluation.

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Section: Cell‐penetrating Peptide Familiesmentioning

confidence: 99%

Section: Cell-penetrating Peptide Familiesmentioning

confidence: 99%

Twenty years of cell‐penetrating peptides: from molecular mechanisms to therapeutics

Heitz

Morris

Divita

2009

British J Pharmacology

768

707

View full text Add to dashboard Cite

show abstract

“…We have chosen PNAs as our model cargo for four reasons: 1) Their size is easily tunable at constant LogD by adjusting the number of nucleobases, 2) They are cell membrane-impermeable on their own (when not linked to a cationic cell-penetrating peptide sequence or to pHLIP), 3) They can be easily labeled with a fluorophore, thereby allowing tracking of their cell delivery and in vivo biodistribution, and 4) They have therapeutic potential as modulators of gene expression. [28][29][30][31] Previously, pHLIP has been used to deliver PNAs that inhibit a microRNA 22 and a long-noncoding RNA 23 , respectively. Although sufficient delivery for a therapeutic effect was achieved in both studies, it is important to note that tumor targeting by either pHLIP-PNA conjugate was not actually demonstrated in vivo.…”

Section: Introductionmentioning

confidence: 99%

Tumor-Targeted, Cytoplasmic Delivery of Large, Polar Molecules Using a pH-Low Insertion Peptide

Svoronos¹,

Bahal

Pereira

et al. 2020

Mol. Pharmaceutics

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Tumor-targeted drug delivery systems offer not only the advantage of an enhanced therapeutic index, but also the possibility of overcoming the limitations that have largely restricted drug design to small, hydrophobic, "drug-like" molecules. Here, we explore the ability of a tumor-targeted delivery system centered on the use of pH-low insertion peptide (pHLIP) to directly deliver moderately polar, multi-kDa molecules into tumor cells. A pHLIP is a short, pH-responsive peptide capable of inserting across a cell membrane to form a transmembrane helix at acidic pH. pHLIP targets the acidic tumor microenvironment with high specificity, and a drug attached to the inserting end of pHLIP can be translocated across the cell membrane during the insertion process.

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“…However, a key issue in use of ONs as therapeutics has been to achieve a sufficient level of intra-cellular delivery, especially in vivo for example within diseased muscle of DMD patients, such that the ON is in significant excess over the RNA target and remains so in order to achieve a high and sustained level of biological activity. Conjugation of the ON to a cell-penetrating peptide (CPP) enhances significantly the activity of both PNA and PMO in cellular and animal models ( 15–19 ). In the case of PMO, an arginine-rich lead peptide has been proposed, (R-Ahx-R) 4 -Ahx-β-Ala (or RXR4XB), where Ahx (X) is aminohexanoyl.…”

Section: Introductionmentioning

confidence: 99%

Improved cell-penetrating peptide–PNA conjugates for splicing redirection in HeLa cells and exon skipping in mdx mouse muscle

Ivanova¹,

Arzumanov²,

Abes³

et al. 2008

Nucleic Acids Research

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160

158

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Steric blocking peptide nucleic acid (PNA) oligonucleotides have been used increasingly for redirecting RNA splicing particularly in therapeutic applications such as Duchenne muscular dystrophy (DMD). Covalent attachment of a cell-penetrating peptide helps to improve cell delivery of PNA. We have used a HeLa pLuc705 cell splicing redirection assay to develop a series of PNA internalization peptides (Pip) conjugated to an 18-mer PNA705 model oligonucleotide with higher activity compared to a PNA705 conjugate with a leading cell-penetrating peptide being developed for therapeutic use, (R-Ahx-R)4. We show that Pip–PNA705 conjugates are internalized in HeLa cells by an energy-dependent mechanism and that the predominant pathway of cell uptake of biologically active conjugate seems to be via clathrin-dependent endocytosis. In a mouse model of DMD, serum-stabilized Pip2a or Pip2b peptides conjugated to a 20-mer PNA (PNADMD) targeting the exon 23 mutation in the dystrophin gene showed strong exon-skipping activity in differentiated mdx mouse myotubes in culture in the absence of an added transfection agent at concentrations where naked PNADMD was inactive. Injection of Pip2a-PNADMD or Pip2b-PNADMD into the tibealis anterior muscles of mdx mice resulted in ∼3-fold higher numbers of dystrophin-positive fibres compared to naked PNADMD or (R-Ahx-R)4-PNADMD.

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Peptide–Peptide Nucleic Acid Conjugates for Modulation of Gene Expression

Cited by 6 publications

References 99 publications

Twenty years of cell‐penetrating peptides: from molecular mechanisms to therapeutics

Twenty years of cell‐penetrating peptides: from molecular mechanisms to therapeutics

Tumor-Targeted, Cytoplasmic Delivery of Large, Polar Molecules Using a pH-Low Insertion Peptide

Improved cell-penetrating peptide–PNA conjugates for splicing redirection in HeLa cells and exon skipping in mdx mouse muscle

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