scholarly journals Combination of Gemcitabine with Cell-Penetrating Peptides: A Pharmacokinetic Approach Using In Silico Tools

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 693
Author(s):  
Ferreira ◽  
Lapa ◽  
Vale
Keyword(s):  
Prediction Models ◽  
Cell Penetrating Peptides ◽  
New Principal ◽  
Wide Range ◽  
Property Scale ◽  
Cell Penetrating ◽  
Penetration Ability ◽  
Z Scores ◽  
Principal Property ◽  
Natural Amino Acids

Gemcitabine is an anticancer drug used to treat a wide range of solid tumors and is a first line treatment for pancreatic cancer. Our group has previously developed novel conjugates of gemcitabine with cell-penetrating peptides (CPP), and here we report some preliminary data regarding the pharmacokinetics of gemcitabine, two gemcitabine-CPP conjugates and respective CPP gathered from GastroPlus™, and analyze these results considering our previous evaluation of gemcitabine release and conjugates’ bioactivity. Additionally, seeking to shed some light on the relation between the penetration ability of CPP and their physicochemical properties, chemical descriptors for the 20 natural amino acids were calculated, a new principal property scale (z-scale) was created and CPP prediction models were developed, establishing quantitative structure-activity relationships (QSAR). The z-scores of the peptides conjugated with gemcitabine are presented and analyzed with the aforementioned data.

Current Delivery Strategies to Improve the Target of Cell Penetrating Peptides Used for Tumor-Related Therapeutics

2018 ◽  
Vol 24 (5) ◽  
pp. 541-548 ◽  
Author(s):  
Fang Zhang ◽  
Dandan Yang ◽  
Shanshan Jiang ◽  
Lei Wu ◽  
Li Qin ◽  
...  
Keyword(s):  
Tumor Therapy ◽  
Cell Penetrating Peptides ◽  
Theoretical Background ◽  
Laboratory Research ◽  
Transport Efficiency ◽  
Promising Tool ◽  
Wide Range ◽  
Cell Penetrating ◽  
Delivery Strategies ◽  
Gain Access

Cell Penetrating Peptides (CPPs) equipped with a high penetrating ability are used as a promising tool to gain access to the cell interior, cross the cell membrane and deliver bioactive small or macromolecular cargos into the cytoplasm or nucleus. The superiority of wide range of applications, high transport efficiency and low biological toxicity make them particularly desirable in laboratory or clinical studies. Previous studies have shown that their non-selectivity and reaction with proteins in plasma hamper their application for tumor therapy, which might adversely affect the treatment effect and even induce some side effects. However, several recent studies have found that various kinds of modifiers of CPPs can effectively increase the target selectivity, reduce cytotoxicity to normal cells and produce multiple antitumor functions due to the different cleavable bonds which are sensitive to the tumor microenvironment or other novel designs. Apparently, these designs of ‘smart’ CPPs appear to be promising in the field of antitumor drug delivery. Here, we review these current improved approaches which mainly involve strategies of physical, chemical as well as biological pathways and we also explain the possible uptake mechanisms of direct penetration, internalization and escape which have been discussed in some publications with specific attention. In addition, some possible problems needed to be considered in the process of improving CPPs are discussed at the end of this review. This study aims to present an overview of the latest progress of CPPs, and provides a comprehensive theoretical background and reference guidance for future laboratory research and clinical application.

scholarly journals Cargo-dependent cytotoxicity and delivery efficacy of cell-penetrating peptides: a comparative study

2007 ◽  
Vol 407 (2) ◽  
pp. 285-292 ◽  
Author(s):  
Samir El-Andaloussi ◽  
Peter Järver ◽  
Henrik J. Johansson ◽  
Ülo Langel
Keyword(s):  
Membrane Integrity ◽  
Cell Penetrating Peptides ◽  
Bioactive Molecules ◽  
Cargo Delivery ◽  
Wide Range ◽  
Cell Penetrating ◽  
Coupling Strategy ◽  
Transactivator Of Transcription

The use of CPPs (cell-penetrating peptides) as delivery vectors for bioactive molecules has been an emerging field since 1994 when the first CPP, penetratin, was discovered. Since then, several CPPs, including the widely used Tat (transactivator of transcription) peptide, have been developed and utilized to translocate a wide range of compounds across the plasma membrane of cells both in vivo and in vitro. Although the field has emerged as a possible future candidate for drug delivery, little attention has been given to the potential toxic side effects that these peptides might exhibit in cargo delivery. Also, no comprehensive study has been performed to evaluate the relative efficacy of single CPPs to convey different cargos. Therefore we selected three of the major CPPs, penetratin, Tat and transportan 10, and evaluated their ability to deliver commonly used cargos, including fluoresceinyl moiety, double-stranded DNA and proteins (i.e. avidin and streptavidin), and studied their effect on membrane integrity and cell viability. Our results demonstrate the unfeasibility to use the translocation efficacy of fluorescein moiety as a gauge for CPP efficiency, since the delivery properties are dependent on the cargo used. Furthermore, and no less importantly, the toxicity of CPPs depends heavily on peptide concentration, cargo molecule and coupling strategy.

scholarly journals Influence of the Dabcyl group on the cellular uptake of cationic peptides: short oligoarginines as efficient cell-penetrating peptides

Amino Acids ◽  
2021 ◽  
Author(s):  
Ildikó Szabó ◽  
Françoise Illien ◽  
Levente E. Dókus ◽  
Mo’ath Yousef ◽  
Zsuzsa Baranyai ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Cell Penetrating Peptides ◽  
Antitumor Drugs ◽  
Short Peptides ◽  
Cationic Peptides ◽  
Wide Range ◽  
Cell Penetrating ◽  
Delivery Vehicles ◽  
Direct Delivery ◽  
Diffuse Distribution

AbstractCell-penetrating peptides (CPPs) are promising delivery vehicles. These short peptides can transport wide range of cargos into cells, although their usage has often limitations. One of them is the endosomatic internalisation and thus the vesicular entrapment. Modifications which increases the direct delivery into the cytosol is highly researched area. Among the oligoarginines the longer ones (n > 6) show efficient internalisation and they are well-known members of CPPs. Herein, we describe the modification of tetra- and hexaarginine with (4–((4–(dimethylamino)phenyl)azo)benzoyl) (Dabcyl) group. This chromophore, which is often used in FRET system increased the internalisation of both peptides, and its effect was more outstanding in case of hexaarginine. The modified hexaarginine may enter into cells more effectively than octaarginine, and showed diffuse distribution besides vesicular transport already at low concentration. The attachment of Dabcyl group not only increases the cellular uptake of the cell-penetrating peptides but it may affect the mechanism of their internalisation. Their conjugates with antitumor drugs were studied on different cells and showed antitumor activity.

scholarly journals Engineering Cell-Permeable Proteins through Insertion of Cell-Penetrating Motifs into Surface Loops

2020 ◽  
Author(s):  
Kuangyu Chen ◽  
Dehua Pei
Keyword(s):  
Mammalian Cells ◽  
Fluorescent Protein ◽  
Tyrosine Phosphatase ◽  
Structural Features ◽  
Cell Penetrating Peptides ◽  
Biologically Active ◽  
Enzyme Replacement ◽  
Loop Region ◽  
Wide Range ◽  
Cell Penetrating

ABSTRACTEffective delivery of proteins into the cytosol and nucleus of mammalian cells would open the door to a wide range of applications including treatment of many currently intractable diseases. However, despite great efforts from numerous investigators and the development of a variety of innovative methods, effective protein delivery in a clinical setting is yet to be accomplished. Herein we report a potentially general approach to engineering cell-permeable proteins by genetically grafting a short cell-penetrating peptide to an exposed loop region of a protein of interest. The grafted peptide is conformationally constrained by the protein structure, sharing the structural features of cyclic cell-penetrating peptides and exhibiting enhanced proteolytic stability and cellular entry efficiency. Insertion of an amphipathic motif, Arg-Arg-Arg-Arg-Trp-Trp-Trp, into the loop regions of enhanced green fluorescent protein (EGFP), protein-tyrosine phosphatase 1B (PTP1B), and purine nucleoside phosphorylase (PNP) rendered all three proteins cell-permeable and biologically active in cellular assays. When added into growth medium, the engineered PTP1B dose-dependently reduced the phosphotyrosine levels of intracellular proteins, while the modified PNP protected PNP-deficient mouse T lymphocytes (NSU-1) against toxic levels of deoxyguanosine, providing a potential enzyme replacement therapy for a rare genetic disease.

scholarly journals Oligoalanine helical callipers for cell penetration

2018 ◽  
Vol 54 (50) ◽  
pp. 6919-6922 ◽  
Author(s):  
Marta Pazo ◽  
Marisa Juanes ◽  
Irene Lostalé-Seijo ◽  
Javier Montenegro
Keyword(s):  
Amino Acids ◽  
Rational Design ◽  
Chemical Space ◽  
Cell Penetrating Peptides ◽  
Short Peptides ◽  
Cell Penetration ◽  
Basic Amino Acids ◽  
Cell Penetrating ◽  
Natural Amino Acids

Even for short peptides that are enriched in basic amino acids, the large chemical space that can be spanned by combinations of natural amino acids hinders the rational design of cell penetrating peptides.

scholarly journals Combination of Cell-Penetrating Peptides with Nanoparticles for Therapeutic Application: A Review

Biomolecules ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 22 ◽  
Author(s):  
Sara Silva ◽  
António Almeida ◽  
Nuno Vale
Keyword(s):  
Small Molecules ◽  
Protein Translocation ◽  
Cell Penetrating Peptides ◽  
Amino Acid Residues ◽  
Therapeutic Application ◽  
New Class ◽  
Wide Range ◽  
Cell Penetrating ◽  
Therapeutic Molecules ◽  
Resistant Strains

Cell-penetrating peptides (CPPs), also known as protein translocation domains, membrane translocating sequences or Trojan peptides, are small molecules of 6 to 30 amino acid residues capable of penetrating biological barriers and cellular membranes. Furthermore, CPP have become an alternative strategy to overcome some of the current drug limitations and combat resistant strains since CPPs are capable of delivering different therapeutic molecules against a wide range of diseases. In this review, we address the recent conjugation of CPPs with nanoparticles, which constitutes a new class of delivery vectors with high pharmaceutical potential in a variety of diseases.

Perspectives and Challenges of Cell-Penetrating Peptides in Effective siRNA Delivery

Nano LIFE ◽  
2014 ◽  
Vol 04 (04) ◽  
pp. 1441016 ◽  
Author(s):  
Zhiqiang Yu ◽  
Bin Yu ◽  
Justin Boy Kaye ◽  
Chenhong Tang ◽  
Shengxi Chen ◽  
...  
Keyword(s):  
Delivery System ◽  
Sirna Delivery ◽  
Cell Penetrating Peptides ◽  
Bioactive Molecules ◽  
Nucleic Acid Delivery ◽  
Cellular Delivery ◽  
Advantages And Disadvantages ◽  
Efficient Delivery ◽  
Wide Range ◽  
Cell Penetrating

Over the last two decades, hundreds of cell penetrating peptides (CPPs) have been intensively developed as drug and nucleic acid delivery vectors. In many cases, however, the efficient delivery of exogenous bioactive molecules through the plasma membrane to their targets remains a tremendous challenging issue. CPPs have attracted tremendous research interest as efficient cellular delivery vehicles due to their intrinsic ability to enter cells and mediate uptake of a wide range of macromolecular cargos, such as proteins, peptides, nucleic acids, drugs and nanoparticle carriers. This review presents and discusses the current perspectives of CPP-mediated siRNA delivery system. We focus on the CPP-mediated siRNA delivery approaches, and particular emphasis is placed on the strategies for the advantages and disadvantages for each delivery approach. Lastly, the cellular uptake mechanisms of CPPs and the specific challenges associated with each delivery system of siRNAs are discussed.

scholarly journals Exploring novel and potent cell penetrating peptides in the proteome of SARS-COV-2 using bioinformatics approaches

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0247396
Author(s):  
Kimia Kardani ◽  
Azam Bolhassani
Keyword(s):  
Drug Delivery ◽  
Half Life ◽  
Web Server ◽  
Cell Penetrating Peptides ◽  
Binding Potential ◽  
Nuclear Localization Sequence ◽  
Web Servers ◽  
Net Charge ◽  
Wide Range ◽  
Cell Penetrating

Among various delivery systems for vaccine and drug delivery, cell-penetrating peptides (CPPs) have been known as a potent delivery system because of their capability to penetrate cell membranes and deliver some types of cargoes into cells. Several CPPs were found in the proteome of viruses such as Tat originated from human immunodeficiency virus-1 (HIV-1), and VP22 derived from herpes simplex virus-1 (HSV-1). In the current study, a wide-range of CPPs was identified in the proteome of SARS-CoV-2, a new member of coronaviruses family, using in silico analyses. These CPPs may play a main role for high penetration of virus into cells and infection of host. At first, we submitted the proteome of SARS-CoV-2 to CellPPD web server that resulted in a huge number of CPPs with ten residues in length. Afterward, we submitted the predicted CPPs to C2Pred web server for evaluation of the probability of each peptide. Then, the uptake efficiency of each peptide was investigated using CPPred-RF and MLCPP web servers. Next, the physicochemical properties of the predicted CPPs including net charge, theoretical isoelectric point (pI), amphipathicity, molecular weight, and water solubility were calculated using protparam and pepcalc tools. In addition, the probability of membrane binding potential and cellular localization of each CPP were estimated by Boman index using APD3 web server, D factor, and TMHMM web server. On the other hand, the immunogenicity, toxicity, allergenicity, hemolytic potency, and half-life of CPPs were predicted using various web servers. Finally, the tertiary structure and the helical wheel projection of some CPPs were predicted by PEP-FOLD3 and Heliquest web servers, respectively. These CPPs were divided into: a) CPP containing tumor homing motif (RGD) and/or tumor penetrating motif (RXXR); b) CPP with the highest Boman index; c) CPP with high half-life (~100 hour) in mammalian cells, and d) CPP with +5.00 net charge. Based on the results, we found a large number of novel CPPs with various features. Some of these CPPs possess tumor-specific motifs which can be evaluated in cancer therapy. Furthermore, the novel and potent CPPs derived from SARS-CoV-2 may be used alone or conjugated to some sequences such as nuclear localization sequence (NLS) for vaccine and drug delivery.

scholarly journals Peptide Stapling Improves the Sustainability of a Peptide-Based Chimeric Molecule That Induces Targeted Protein Degradation

2021 ◽  
Vol 22 (16) ◽  
pp. 8772
Author(s):  
Hidetomo Yokoo ◽  
Nobumichi Ohoka ◽  
Mami Takyo ◽  
Takahito Ito ◽  
Keisuke Tsuchiya ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Estrogen Receptor Alpha ◽  
Cell Penetrating Peptides ◽  
Side Chain ◽  
Binding Peptide ◽  
Stapled Peptide ◽  
Chimeric Peptide ◽  
Cell Penetrating ◽  
Natural Amino Acids ◽  
Peptide Stapling

Peptide-based target protein degradation inducers called PROTACs/SNIPERs have low cell penetrability and poor intracellular stability as drawbacks. These shortcomings can be overcome by easily modifying these peptides by conjugation with cell penetrating peptides and side-chain stapling. In this study, we succeeded in developing the stapled peptide stPERML-R7, which is based on the estrogen receptor alpha (ERα)-binding peptide PERML and composed of natural amino acids. stPERML-R7, which includes a hepta-arginine motif and a hydrocarbon stapling moiety, showed increased α-helicity and similar binding affinity toward ERα when compared with those of the parent peptide PERML. Furthermore, we used stPERML-R7 to develop a peptide-based degrader LCL-stPERML-R7 targeting ERα by conjugating stPERML-R7 with a small molecule LCL161 (LCL) that recruits the E3 ligase IAPs to induce proteasomal degradation via ubiquitylation. The chimeric peptide LCL-stPERML-R7 induced sustained degradation of ERα and potently inhibited ERα-mediated transcription more effectively than the unstapled chimera LCL-PERML-R7. These results suggest that a stapled structure is effective in maintaining the intracellular activity of peptide-based degraders.

Empirical comparison and analysis of web-based cell-penetrating peptide prediction tools

2019 ◽  
Vol 21 (2) ◽  
pp. 408-420 ◽  
Author(s):  
Ran Su ◽  
Jie Hu ◽  
Quan Zou ◽  
Balachandran Manavalan ◽  
Leyi Wei
Keyword(s):  
Prediction Models ◽  
Cell Penetrating Peptides ◽  
Web Based ◽  
Practical Applications ◽  
Prediction Tools ◽  
Cell Penetrating ◽  
Potential Applications ◽  
Peptide Prediction

Abstract Cell-penetrating peptides (CPPs) facilitate the delivery of therapeutically relevant molecules, including DNA, proteins and oligonucleotides, into cells both in vitro and in vivo. This unique ability explores the possibility of CPPs as therapeutic delivery and its potential applications in clinical therapy. Over the last few decades, a number of machine learning (ML)-based prediction tools have been developed, and some of them are freely available as web portals. However, the predictions produced by various tools are difficult to quantify and compare. In particular, there is no systematic comparison of the web-based prediction tools in performance, especially in practical applications. In this work, we provide a comprehensive review on the biological importance of CPPs, CPP database and existing ML-based methods for CPP prediction. To evaluate current prediction tools, we conducted a comparative study and analyzed a total of 12 models from 6 publicly available CPP prediction tools on 2 benchmark validation sets of CPPs and non-CPPs. Our benchmarking results demonstrated that a model from the KELM-CPPpred, namely KELM-hybrid-AAC, showed a significant improvement in overall performance, when compared to the other 11 prediction models. Moreover, through a length-dependency analysis, we find that existing prediction tools tend to more accurately predict CPPs and non-CPPs with the length of 20–25 residues long than peptides in other length ranges.

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