Status update in the use of cell-penetrating peptides for the delivery of macromolecular therapeutics

Kurrikoff, Kaido; Vunk, Birgit; Langel, Ülo

doi:10.1080/14712598.2021.1823368

Cited by 59 publications

(47 citation statements)

References 53 publications

(65 reference statements)

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“…The mechanisms of the uptake of transportan and its modifications are not exceptions; one can find attempts to understand its trans-membrane delivery with multiple methods in comparison with several other CPPs [ 116 , 117 ]; see Table 1 and the detailed examples below.…”

Section: Mechanismsmentioning

confidence: 99%

Cell-Penetrating Peptides and Transportan

Langel

2021

Pharmaceutics

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In the most recent 25–30 years, multiple novel mechanisms and applications of cell-penetrating peptides (CPP) have been demonstrated, leading to novel drug delivery systems. In this review, I present a brief introduction to the CPP area with selected recent achievements. This is followed by a nostalgic journey into the research in my own laboratories, which lead to multiple CPPs, starting from transportan and paving a way to CPP-based therapeutic developments in the delivery of bio-functional materials, such as peptides, proteins, vaccines, oligonucleotides and small molecules, etc.

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Section: Mechanismsmentioning

confidence: 99%

Cell-Penetrating Peptides and Transportan

Langel

2021

Pharmaceutics

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“…Then, (KFF) 2 or (KFF) 3 are removed from the conjugate and the PNA oligomer naked or bound to a KFF tripeptide penetrates the inner membrane in a SmbA protein-dependent process [54,55]. Descriptions of mechanisms of internalization and uses of CPPs to transfer cargo inside different kinds of cells can be found in recent reviews [56][57][58][59].…”

Section: External Guide Sequence (Egs) Technologymentioning

confidence: 99%

“…While CPPs had been very useful for delivery of a variety of oligonucleotide analogs to diverse cells [56][57][58][59], their conjugation to LNAs was challenging due to the charged nature of these analogs and overcoming this stumbling block delayed the possibility of testing LNA-containing oligomers in cells in culture. The active LNA/deoxyribonucleotides gapmers were conjugated to the (RXR) 4 XB (R, arginine; X, 6 aminohexanoic acid; B, betaalanine) peptide, a CPP for the delivery of oligonucleotides to bacterial cells [60,61].…”

Section: External Guide Sequence (Egs) Technologymentioning

confidence: 99%

Silencing Antibiotic Resistance with Antisense Oligonucleotides

2021

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Antisense technologies consist of the utilization of oligonucleotides or oligonucleotide analogs to interfere with undesirable biological processes, commonly through inhibition of expression of selected genes. This field holds a lot of promise for the treatment of a very diverse group of diseases including viral and bacterial infections, genetic disorders, and cancer. To date, drugs approved for utilization in clinics or in clinical trials target diseases other than bacterial infections. Although several groups and companies are working on different strategies, the application of antisense technologies to prokaryotes still lags with respect to those that target other human diseases. In those cases where the focus is on bacterial pathogens, a subset of the research is dedicated to produce antisense compounds that silence or reduce expression of antibiotic resistance genes. Therefore, these compounds will be adjuvants administered with the antibiotic to which they reduce resistance levels. A varied group of oligonucleotide analogs like phosphorothioate or phosphorodiamidate morpholino residues, as well as peptide nucleic acids, locked nucleic acids and bridge nucleic acids, the latter two in gapmer configuration, have been utilized to reduce resistance levels. The major mechanisms of inhibition include eliciting cleavage of the target mRNA by the host’s RNase H or RNase P, and steric hindrance. The different approaches targeting resistance to β-lactams include carbapenems, aminoglycosides, chloramphenicol, macrolides, and fluoroquinolones. The purpose of this short review is to summarize the attempts to develop antisense compounds that inhibit expression of resistance to antibiotics.

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“…CPPs are relatively short cationic, amphipathic peptides ( Kurrikoff et al, 2020 ) and are being widely used for intracellular drug delivery for a wide range of cell-impermeable cargoes, such as therapeutic antisense oligonucleotides (ASOs). The conjugation of CPPs to ASOs has been shown to enhance their cell permeability, intracellular bioavailability, and subsequently, an increase in their therapeutic efficacy ( Tajik-Ahmadabad et al, 2017 ; Klein et al, 2019 ; Nikan et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Modular Synthesis of Trifunctional Peptide-oligonucleotide Conjugates via Native Chemical Ligation

et al. 2021

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Cell penetrating peptides (CPPs) are being increasingly used as efficient vectors for intracellular delivery of biologically active agents, such as therapeutic antisense oligonucleotides (ASOs). Unfortunately, ASOs have poor cell membrane permeability. The conjugation of ASOs to CPPs have been shown to significantly improve their cellular permeability and therapeutic efficacy. CPPs are often covalently conjugated to ASOs through a variety of chemical linkages. Most of the reported approaches for ligation of CPPs to ASOs relies on methodologies that forms non-native bond due to incompatibility with in-solution phase conjugation. These approaches have low efficiency and poor yields. Therefore, in this study, we have exploited native chemical ligation (NCL) as an efficient strategy for synthesizing CPP-ASO conjugates. A previously characterized CPP [ApoE(133–150)] was used to conjugate to a peptide nucleic acid (PNA) sequence targeting human survival motor neuron-2 (SMN2) mRNA which has been approved by the FDA for the treatment of spinal muscular atrophy. The synthesis of ApoE(133–150)-PNA conjugate using chemo-selective NCL was highly efficient and the conjugate was obtained in high yield. Toward synthesizing trifunctional CPP-ASO conjugates, we subsequently conjugated different functional moieties including a phosphorodiamidate morpholino oligonucleotide (PMO), an additional functional peptide or a fluorescent dye (Cy5) to the thiol that was generated after NCL. The in vitro analysis of the bifunctional CPP-PNA and trifunctional CPP-(PMO)-PNA, CPP-(peptide)-PNA and CPP-(Cy5)-PNA showed that all conjugates are cell-permeable and biologically active. Here we demonstrated chemo-selective NCL as a highly efficient and superior conjugation strategy to previously published methods for facile solution-phase synthesis of bi-/trifunctional CPP-ASO conjugates.

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Status update in the use of cell-penetrating peptides for the delivery of macromolecular therapeutics

Cited by 59 publications

References 53 publications

Cell-Penetrating Peptides and Transportan

Cell-Penetrating Peptides and Transportan

Silencing Antibiotic Resistance with Antisense Oligonucleotides

Modular Synthesis of Trifunctional Peptide-oligonucleotide Conjugates via Native Chemical Ligation

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