scholarly journals Improved Efficacy of Fosmidomycin against Plasmodium and Mycobacterium Species by Combination with the Cell-Penetrating Peptide Octaarginine

2013 ◽  
Vol 57 (10) ◽  
pp. 4689-4698 ◽  
Author(s):  
Christof Sparr ◽  
Nirupam Purkayastha ◽  
Beata Kolesinska ◽  
Martin Gengenbacher ◽  
Borko Amulic ◽  
...  
Keyword(s):  
Cell Penetrating Peptides ◽  
Isoprenoid Biosynthesis ◽  
Cell Permeability ◽  
Target Cells ◽  
Intracellular Pathogens ◽  
Content Type ◽  
Chemical Genetic ◽  
Nonmevalonate Pathway ◽  
Cell Penetrating ◽  
Covalently Linked

ABSTRACTCellular drug delivery can improve efficacy and render intracellular pathogens susceptible to compounds that cannot permeate cells. The transport of physiologically active compounds across membranes into target cells can be facilitated by cell-penetrating peptides (CPPs), such as oligoarginines. Here, we investigated whether intracellular delivery of the drug fosmidomycin can be improved by combination with the CPP octaarginine. Fosmidomycin is an antibiotic that inhibits the second reaction in the nonmevalonate pathway of isoprenoid biosynthesis, an essential pathway for many obligate intracellular pathogens, including mycobacteria and apicomplexan parasites. We observed a strict correlation between octaarginine host cell permeability and its ability to improve the efficacy of fosmidomycin.Plasmodium bergheiliver-stage parasites were only partially susceptible to an octaarginine-fosmidomycin complex. Similarly,Toxoplasma gondiiwas only susceptible during the brief extracellular stages. In marked contrast, a salt complex of octaarginine and fosmidomycin greatly enhanced efficacy against blood-stagePlasmodium falciparum. This complex and a covalently linked conjugate of octaarginine and fosmidomycin also reverted resistance ofMycobacteriato fosmidomycin. These findings provide chemical genetic evidence for vital roles of the nonmevalonate pathway of isoprenoid biosynthesis in a number of medically relevant pathogens. Our results warrant further investigation of octaarginine as a delivery vehicle and alternative fosmidomycin formulations for malaria and tuberculosis drug development.

scholarly journals Bacterium-Derived Cell-Penetrating Peptides Deliver Gentamicin To Kill Intracellular Pathogens

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Marta Gomarasca ◽  
Thaynan F. C. Martins ◽  
Lilo Greune ◽  
Philip R. Hardwidge ◽  
M. Alexander Schmidt ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Antimicrobial Agents ◽  
Shigella Flexneri ◽  
Cell Penetrating Peptides ◽  
Biologically Active ◽  
Intracellular Pathogens ◽  
Content Type ◽  
Cell Penetrating ◽  
Serovar Typhimurium ◽  
Therapeutic Tools

ABSTRACT Commonly used antimicrobials show poor cellular uptake and often have limited access to intracellular targets, resulting in low antimicrobial activity against intracellular pathogens. An efficient delivery system to transport these drugs to the intracellular site of action is needed. Cell-penetrating peptides (CPPs) mediate the internalization of biologically active molecules into the cytoplasm. Here, we characterized two CPPs, α1H and α2H, derived from the Yersinia enterocolitica YopM effector protein. These CPPs, as well as Tat (trans-activator of transcription) from HIV-1, were used to deliver the antibiotic gentamicin to target intracellular bacteria. The YopM-derived CPPs penetrated different endothelial and epithelial cells to the same extent as Tat. CPPs were covalently conjugated to gentamicin, and CPP-gentamicin conjugates were used to target infected cells to kill multiple intracellular Gram-negative pathogenic bacteria, including Escherichia coli K1, Salmonella enterica serovar Typhimurium, and Shigella flexneri. Taken together, CPPs show great potential as delivery vehicles for antimicrobial agents and may contribute to the generation of new therapeutic tools to treat infectious diseases caused by intracellular pathogens.

scholarly journals Cell-Penetrating Peptides as a Tool for the Cellular Uptake of a Genetically Modified Nitroreductase for use in Directed Enzyme Prodrug Therapy

2019 ◽  
Vol 10 (4) ◽  
pp. 45 ◽  
Author(s):  
Anderson ◽  
Hobbs ◽  
Gwenin ◽  
Ball ◽  
Bennie ◽  
...  
Keyword(s):  
Magnetic Nanoparticle ◽  
Genetically Modified ◽  
Cell Penetrating Peptides ◽  
Target Cells ◽  
Tumour Site ◽  
Enzyme Prodrug Therapy ◽  
Delivery Vector ◽  
Cell Penetrating ◽  
Subsequent Activation ◽  
Potential Use

Directed enzyme prodrug therapy (DEPT) involves the delivery of a prodrug-activating enzyme to a solid tumour site, followed by the subsequent activation of an administered prodrug. One of the most studied enzyme–prodrug combinations is the nitroreductase from Escherichia coli (NfnB) with the prodrug CB1954 [5-(aziridin-1-yl)-2,4-dinitro-benzamide]. One of the major issues faced by DEPT is the ability to successfully internalize the enzyme into the target cells. NfnB has previously been genetically modified to contain cysteine residues (NfnB-Cys) which bind to gold nanoparticles for a novel DEPT therapy called magnetic nanoparticle directed enzyme prodrug therapy (MNDEPT). One cellular internalisation method is the use of cell-penetrating peptides (CPPs), which aid cellular internalization of cargo. Here the cell-penetrating peptides: HR9 and Pep-1 were tested for their ability to conjugate with NfnB-Cys. The conjugates were further tested for their potential use in MNDEPT, as well as conjugating with the delivery vector intended for use in MNDEPT and tested for the vectors capability to penetrate into cells.

scholarly journals Intrinsically cell-penetrating multivalent and multitargeting ligands for myotonic dystrophy type 1

2019 ◽  
Vol 116 (18) ◽  
pp. 8709-8714 ◽  
Author(s):  
JuYeon Lee ◽  
Yugang Bai ◽  
Ullas V. Chembazhi ◽  
Shaohong Peng ◽  
Kevin Yum ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Trinucleotide Repeat ◽  
Cell Penetrating Peptides ◽  
Cell Permeability ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Multivalent Ligands ◽  
Biological Studies ◽  
Cell Penetrating

Developing highly active, multivalent ligands as therapeutic agents is challenging because of delivery issues, limited cell permeability, and toxicity. Here, we report intrinsically cell-penetrating multivalent ligands that target the trinucleotide repeat DNA and RNA in myotonic dystrophy type 1 (DM1), interrupting the disease progression in two ways. The oligomeric ligands are designed based on the repetitive structure of the target with recognition moieties alternating with bisamidinium groove binders to provide an amphiphilic and polycationic structure, mimicking cell-penetrating peptides. Multiple biological studies suggested the success of our multivalency strategy. The designed oligomers maintained cell permeability and exhibited no apparent toxicity both in cells and in mice at working concentrations. Furthermore, the oligomers showed important activities in DM1 cells and in a DM1 liver mouse model, reducing or eliminating prominent DM1 features. Phenotypic recovery of the climbing defect in adult DM1Drosophilawas also observed. This design strategy should be applicable to other repeat expansion diseases and more generally to DNA/RNA-targeted therapeutics.

Cyclic, Cell-Penetrating Peptides Tailor-Made for the Creation of Peptide Libraries with Intrinsic Cell Permeability

2020 ◽  
Author(s):  
Nicolas A. Abrigo ◽  
Kara Dods ◽  
Koushambi Mitra ◽  
Kaylee Newcomb ◽  
Anthony Le ◽  
...  
Keyword(s):  
Cyclic Peptide ◽  
Cell Penetrating Peptides ◽  
Peptide Libraries ◽  
Cell Permeability ◽  
Side Chain ◽  
High Affinity ◽  
Cell Penetrating ◽  
The Creation ◽  
Intracellular Targets ◽  
Macrocyclic Peptide

<p>The discovery of high-affinity peptides to many intracellular targets has become feasible through the development of diverse macrocyclic peptide libraries. But lack of cell permeability is a key feature hampering the use of these peptides as therapeutics. Here, we develop a set of small, cyclic peptide carriers that efficiently carry cargoes into the cytosol. These peptides are cyclized via side-chain alkylation, which makes them ideal for the creation of diverse mRNA or phage-displayed libraries with intrinsic cell permeability.</p>

Cyclic, Cell-Penetrating Peptides Tailor-Made for the Creation of Peptide Libraries with Intrinsic Cell Permeability

2020 ◽  
Author(s):  
Nicolas A. Abrigo ◽  
Kara Dods ◽  
Koushambi Mitra ◽  
Kaylee Newcomb ◽  
Anthony Le ◽  
...  
Keyword(s):  
Cyclic Peptide ◽  
Cell Penetrating Peptides ◽  
Peptide Libraries ◽  
Cell Permeability ◽  
Side Chain ◽  
High Affinity ◽  
Cell Penetrating ◽  
The Creation ◽  
Intracellular Targets ◽  
Macrocyclic Peptide

<p>The discovery of high-affinity peptides to many intracellular targets has become feasible through the development of diverse macrocyclic peptide libraries. But lack of cell permeability is a key feature hampering the use of these peptides as therapeutics. Here, we develop a set of small, cyclic peptide carriers that efficiently carry cargoes into the cytosol. These peptides are cyclized via side-chain alkylation, which makes them ideal for the creation of diverse mRNA or phage-displayed libraries with intrinsic cell permeability.</p>

scholarly journals Impact of different cell penetrating peptides on the efficacy of antisense therapeutics for targeting intracellular pathogens

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Mostafa F. N. Abushahba ◽  
Haroon Mohammad ◽  
Shankar Thangamani ◽  
Asmaa A. A. Hussein ◽  
Mohamed N. Seleem
Keyword(s):  
Cell Penetrating Peptides ◽  
Intracellular Pathogens ◽  
Cell Penetrating

scholarly journals The Utilization of Cell-Penetrating Peptides in the Intracellular Delivery of Viral Nanoparticles

Materials ◽  
2019 ◽  
Vol 12 (17) ◽  
pp. 2671 ◽  
Author(s):  
Jana Váňová ◽  
Alžběta Hejtmánková ◽  
Marie Hubálek Kalbáčová ◽  
Hana Španielová
Keyword(s):  
Genetic Material ◽  
Cell Types ◽  
Cell Penetrating Peptides ◽  
Target Cells ◽  
Current State ◽  
Cargo Delivery ◽  
Viral Particles ◽  
Cell Penetrating ◽  
Viral Nanoparticles ◽  
Immunogenic Properties

Viral particles (VPs) have evolved so as to efficiently enter target cells and to deliver their genetic material. The current state of knowledge allows us to use VPs in the field of biomedicine as nanoparticles that are safe, easy to manipulate, inherently biocompatible, biodegradable, and capable of transporting various cargoes into specific cells. Despite the fact that these virus-based nanoparticles constitute the most common vectors used in clinical practice, the need remains for further improvement in this area. The aim of this review is to discuss the potential for enhancing the efficiency and versatility of VPs via their functionalization with cell-penetrating peptides (CPPs), short peptides that are able to translocate across cellular membranes and to transport various substances with them. The review provides and describes various examples of and means of exploitation of CPPs in order to enhance the delivery of VPs into permissive cells and/or to allow them to enter a broad range of cell types. Moreover, it is possible that CPPs are capable of changing the immunogenic properties of VPs, which could lead to an improvement in their clinical application. The review also discusses strategies aimed at the modification of VPs by CPPs so as to create a useful cargo delivery tool.

scholarly journals Generalized displacement of DNA- and RNA-binding factors mediates the toxicity of arginine-rich cell-penetrating peptides

2018 ◽  
Author(s):  
V. Lafarga ◽  
O. Sirozh ◽  
I. Díaz-López ◽  
M. Hisaoka ◽  
E. Zarzuela ◽  
...  
Keyword(s):  
Dna Binding ◽  
Nucleic Acids ◽  
Rna Binding ◽  
Cell Penetrating Peptides ◽  
Target Cells ◽  
Dna And Rna ◽  
Cell Penetrating ◽  
Dna Binding Factors ◽  
Dna Replication And Repair ◽  
Rna And Dna

ABSTRACTDue to their capability to transport chemicals or proteins into target cells, cell-penetrating peptides (CPPs) are being developed as therapy delivery tools. However, and despite their interesting properties, arginine-rich CPPs often show toxicity for reasons that remain poorly understood. Using a (PR)n dipeptide repeat that has been linked to amyotrophic-lateral sclerosis (ALS) as a model of an arginine-rich CPP, we here show that the presence of (PR)n leads to a generalized displacement of RNA- and DNA-binding proteins from chromatin and mRNA. Accordingly, any reaction involving nucleic acids such as RNA transcription, translation, splicing and degradation or DNA replication and repair are impaired by the presence of the CPP. Interestingly, the effects of (PR)n are fully mimicked by PROTAMINE, a small arginine-rich protein that displaces histones from chromatin during spermatogenesis. We propose that widespread coating of nucleic acids and consequent displacement of RNA- and DNA-binding factors from chromatin and mRNA accounts for the toxicity of arginine-rich CPPs, including those that have been recently associated to the onset of ALS.

scholarly journals Identification of Cell-Penetrating Peptides That Are Bactericidal to Neisseria meningitidis and Prevent Inflammatory Responses upon Infection

2013 ◽  
Vol 57 (8) ◽  
pp. 3704-3712 ◽  
Author(s):  
Olaspers Sara Eriksson ◽  
Miriam Geörg ◽  
Hong Sjölinder ◽  
Rannar Sillard ◽  
Staffan Lindberg ◽  
...  
Keyword(s):  
Neisseria Meningitidis ◽  
Inflammatory Responses ◽  
Structural Features ◽  
Cell Penetrating Peptides ◽  
Amphipathic Peptide ◽  
Content Type ◽  
Sytox Green ◽  
Cell Penetrating ◽  
Fast Progression

ABSTRACTMeningococcal disease is characterized by a fast progression and a high mortality rate. Cell-penetrating peptides (CPPs), developed as vectors for cargo delivery into eukaryotic cells, share structural features with antimicrobial peptides. A screen identified two CPPs, transportan-10 (TP10) and model amphipathic peptide (MAP), with bactericidal action againstNeisseria meningitidis. Both peptides were active in human whole blood at micromolar concentrations, while hemolysis remained negligible. Additionally, TP10 exhibited significant antibacterial activityin vivo. Uptake of SYTOX green into live meningococci was observed within minutes after TP10 treatment, suggesting that TP10 may act by membrane permeabilization. Apart from its bactericidal activity, TP10 suppressed inflammatory cytokine release from macrophages infected withN. meningitidisas well as from macrophages stimulated with enterobacterial and meningococcal lipopolysaccharide (LPS). Finally, incubation with TP10 reduced the binding of LPS to macrophages. This novel endotoxin-inhibiting property of TP10, together with its antimicrobial activityin vivo, indicates the possibility to design peptide-based therapies for infectious diseases.

scholarly journals Development of Cell Penetrating Peptides for Effective Delivery of Recombinant Factors into Target Cells

2020 ◽  
Vol 27 (11) ◽  
pp. 1092-1101
Author(s):  
Ubashini Vijakumaran ◽  
Fazlina Nordin ◽  
Zariyantey Abdul Hamid ◽  
Maha Abdullah ◽  
Tye Gee Jun
Keyword(s):  
Cell Membrane ◽  
Protective Layer ◽  
Cell Penetrating Peptides ◽  
Target Cells ◽  
Cell Penetrating ◽  
Effective Delivery ◽  
Natural And Synthetic

The cell membrane is a protective layer that strictly controls the passage of molecules restricting the delivery of biomolecules such as drugs, oligonucleotides, peptides, and siRNA into the cells. This shortcoming has been overcome by the discovery of Cell-Penetrating Peptides (CPPs) that has undergone 30 years of evolution. To date, CPPs are largely modified to improve its efficacy and to suit the different delivery applications. The modes of CPPs penetration are still an unresolved mystery and requires further investigations to increase its effectiveness and to diversify its use. Despite having huge potential as a biomolecule carrier, CPPs also have some drawbacks. In this review, the natural and synthetic CPPs, the modifications that have been conducted on CPPs to improve its efficacy, its extended applications, modes of penetration and limitation as well as challenges will be discussed.

Sign in / Sign up

Export Citation Format

Share Document