Cell Penetrating Peptides for Gene Therapy: History
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Subjects: Medicine, Research & Experimental
Contributor:
Maliha Zahid

Cell penetrating peptides (CPPs), also known as protein transduction domains (PTDs), first identified ~25 years ago, are small, 6–30 amino acid long, synthetic, or naturally occurring peptides, able to carry variety of cargoes across the cellular membranes in an intact, functional form. Since their initial description and characterization, the field of cell penetrating peptides as vectors has exploded. The cargoes they can deliver range from other small peptides, full-length proteins, nucleic acids including RNA and DNA, liposomes, nanoparticles, and viral particles as well as radioisotopes and other fluorescent probes for imaging purposes.

  • cell penetrating peptides
  • protein transduction domains
  • gene therapy
  • small interfering RNA

1. Introduction

The plasma membrane of a cell is essential to its identity and survival, but at the same time presents a barrier to intracellular delivery of potentially diagnostic or therapeutic cargoes. Therefore, the development of approaches to deliver functional cargoes, be they peptides, proteins, nucleic acids, or nanoparticles across cell membranes, a process termed protein transduction, has wide-reaching research and clinical implications. The ability of Trans-Activator of Transcription (Tat) protein of the Human Immunodeficiency Virus (HIV) to transduce cultured cells and lead to viral gene expression [1][2] without requiring a receptor was the first example of a protein that naturally employs a portion of itself to achieve cell penetration and lead to intracellular delivery of the entire HIV viral particle. The chemical cross-linking of a full-length Tat protein to multiple different proteins such as horseradish peroxidase, ß-galactosidase, RNase A and domain III of Pseudomonas exotoxin A served to demonstrate the ability of Tat protein to ferry other large cargoes across the cell membrane [3]. Similarly, the homeobox Antennapedia (Antp) transcription factor of Drosophila melanogaster was demonstrated to enter nerve cells in a receptor independent manner where it could then regulate neural morphogenesis [4]. Mapping of the domains within Tat and Antp responsible for the observed transduction led to the identification of the first two cell penetrating peptides (CPPs): the 11 amino acid cationic domain of HIV-1 Tat protein (YGRKKRRQRRR) [5] and the 16 amino acid sequence from the third helix of the Antennapedia domain (RQIKIWFQNRRMKWKK) termed Antp or penetratin [6]. Subsequently, the ability of the small part of the full-length Tat protein to deliver cargoes, including other full length proteins and even large multimeric protein complexes across cell membranes in culture and in vivo following systemic delivery in mice [7] was documented, further highlighting the delivery potential of these unique peptides. Since then, the number of peptides, both cell-specific and non-specific, reported as having cell penetrating properties has increased exponentially [8]. This is particularly true for a wide spectrum of cationic peptides that primarily rely on their cationic charge to interact with proteoglycans on the cell surface. There has been intense interest in identifying both new cell-specific CPPs, as well as strategies to make Tat and other non-specific CPPs act in a more cell-specific manner by taking advantage of tissue characteristics, mostly in the context of cancer.

2. Types of CPPs

2.1. Non-Cell-Specific CPPs

CPPs are broadly categorized into non-cell-specific and cell-specific peptides with great sequence heterogeneity (Table 1). The non-cell-specific CPPs can be sub-classified into three classes: cationic, hydrophobic, and amphipathic. Tat and Antp are cationic peptides, rich in arginine and lysine, with the longer Antp peptide having a more defined 3D structure. In addition to these naturally occurring CPP sequences, synthetic cationic peptides including homopolymers of arginine [9], lysine [10] and/or the cationic, amino acid ornithine [11] were demonstrated to function as effective transduction peptides. Even histidine, which becomes protonated at low pH, can function as a CPP at pH below 6.0 and has been used for delivery into tumor cells with lower pH [12]. Arginine-based homopolymers ranging from 6 to 12 amino acids function as CPPs with 8–10 amino acid length identified as having the highest transduction ability [13]. Similarly, 8-mer homopolymers of lysine transduce a variety of cell types with similar efficiencies as homopolymers of arginine [14]. There is a definite optimum length for these homopolymers with greater than 12 amino acids showing reduced transduction efficiency. Unlike the acute cellular toxicity elicited by long poly-lysine molecules, short lysine homopolymers (6–12 mers) have no demonstrable cytotoxic effects, even at high concentrations [10]. Thus, it appears that too little or too much cationic charge within a short region negatively affects transduction.
Table 1. Classification of Cell Penetrating Peptides.

CPPs-Non-Tissue Specific

Peptide Sequence

Origin

Cationic

    

Tat [5]

GRKKRRQRRRPPQ

HIV Tat Protein

Ant [6]

RQIKIWFQNRRMKWKK

Antennapedia homeodomain

8-Arginine [9]

RRRRRRRR

n/a

8-Lysine [10]

KKKKKKKK

n/a

PTD-5 [14]

RRQRRTSKLMKR

Phage display

Hydrophobic

    

Transportan [15]

GWTLNSAGYLLGKINLKALAALAKKIL

Galanin and mastoparan

MAP [16]

KLALKLALKALKAALKLA

Galanin and mastoparan

TP10 [17]

AGYLLGKINLKALAALAKKIL

  

Pep-7 [18]

SDLWEMMMVSLACQY

CHL8 peptide

Amphipathic

    

Azurin p18 [19]

LSTAADMQGVVTDGMASG

Azurin

Azurin p28 [20]

LSTAADMQGVVTDGMASGLDKDYLKPDD

Azurin

hCT18-32 [21]

KFHTFPQTAIGVGAP

Calcitonin

Bac 7 [22]

RRIRPRPPRLPRPRPRPLPFPRPG

Bactenecin

CPPs-Tissue Specific

Peptide Sequence

Origin

CTP [23][24]

APWHLSSQYSRT

Phage display

K5-FGF [25]

AAVALLPAVLLALLP

Phage display

HAP-1 [26]

SFHQFARATLAS

Phage display

293P-1 [27]

SNNNVRPIHIWP

Phage display

Vascular Endothelium [28]

SIGYPLP

Phage display
Amphipathic CPPs are chimeric peptides generated by attaching the hydrophobic domain of the CPP to a nuclear localizing signal (NLS) such as the SV40 NLS through a covalent bond [29]. Usually, hydrophobic CPPs are derived from signal peptide sequences. Signal peptides that allow proteins to be secreted from cells can also facilitate entry of the proteins back across the membrane into cells. Examples of hydrophobic transduction peptides identified to date include leader sequences for keratinocyte growth factor and fibroblast growth factor [30], but likely most leader sequences of secreted proteins could potentially function as CPPs.
Interestingly, even certain pathogenic bacteria use CPPs for delivery of bacterial effector proteins into different types of mammalian cells. For example, the pathogenic bacteria Yersinia enterocolitica encodes for the anti-inflammatory protein YopM with two alpha helices, α1H and α2H, in its amino terminus that function as CPPs similar to Antp [31][32][33]. Similarly, Shigella and Salmonella encode for immune effector proteins that can also enter cells efficiently to modulate the immune response [33].

2.2. Cell-Specific CPPs

The other major sub-classification is cell-specific CPPs, identified through different screening methods including plasmid, microorganism surface, ribosome, or phage display of large peptide libraries. The advantage of this approach is that a priori knowledge of a binding partner is not necessary. Such cell-specific CPPs circumvent the issues associated with the non-cell specific CPPs, namely non-specific cellular uptake leading to off-target side effects and the need to administer high doses of CPPs to achieve adequate levels in target organs or cell types of interest. Such high doses are necessary in order for a small fraction of CPPs to escape the liver, kidney, and the reticuloendothelial system to reach the target organ of interest. Such an approach would be particularly troublesome if the target is the brain or a poorly vascularized tissue. Thus, developing tissue or cell-specific CPPs would be particularly attractive as it would improve the efficacy of the delivered cargo with less off-target effects while reducing the overall dose needed, which would be particularly beneficial when scaling up from small to larger animal models, and ultimately for human clinical trials.
Another approach to circumventing this issue is by delivering non-tissue specific CPP bearing cargo in a pro-drug fashion that can be activated under certain conditions or specific environments. This is only feasible if a specific cell type expresses a unique enzymatic activity such as viral or disease specific proteases [34]. Another approach is local delivery (e.g., intra-tumoral, intra-articular, intra-muscular, intra-ocular, intra-tracheal, intra-dermal, etc.) to limit the transduction activity of non-specific CPPs to specific sites. This would depend on and be limited to a specific application or situation and would be feasible only if the target cell is located in an accessible site with limited diffusion such as topical delivery for dermatological applications, the eye for ophthalmological applications [35][36][37], joints for arthritis/degenerative conditions [26], and directly into tumors [38].

3. Identification of Tissue Specific CPPs

Cell-specific CPPs were identified predominantly by using peptide phage display libraries to screen for peptides able to target specific cell types. The concept of phage display was first proposed by Smith in 1985 [39]. Following this initial report, combinatorial peptide libraries of various lengths using different types of phages (M13, T7) have been used successfully to identify peptides able to facilitate internalization of intact phage. Alternatively, plasmid, antibodies, microorganism surface or ribosome displays of peptide libraries have been employed as well. Phage display requires exposing the target cell or tissue of interest to a large, randomized phage library in which one of the envelope proteins used by the phage for internalization has been modified to display linear or cyclic peptides of various lengths and randomized amino acid sequences [40]. The internalized phage can then be isolated, expanded and used in subsequent rounds of screening. Usually 3–5 rounds of screening results in enrichment of a small number of peptides identifiable by DNA sequencing of the recovered phage. This approach requires enriching for a specific, small subset of phage from a very large library. As such, false positives are a concern and have to be discerned from phage that is indeed bound and internalized by the target cell type. One approach to circumvent this problem is to carry out the first cycle in cell culture using relevant cell types in order to reduce the likelihood of false positives. Subsequent cycles can then be carried out in vivo using the enriched pool from the in vitro cycle [40][23][41]. Such an approach has led to the identification of peptides targeting vascular endothelium [28], synovial tissue [26], dendritic cells [42], pancreatic islet cells [43] and cardiac myocytes [23], and has identified NRG (Asparginine-Arginine-Glycine) and RGD (Arginine-Glycine-Aspartic acid) motifs that target phage to tumor vasculature in nude tumor-bearing mice [44].

4. Mechanisms of Transduction

Despite intense study of CPPs, the specific pathway(s) involved in facilitating transduction remain elusive. CPPs are short in length, making the use of standard techniques for identifying binding targets on the cell surface more challenging. Additionally, their rapid cell entry, occurring within minutes at physiological conditions, makes analysis difficult. It is likely that a non-cell specific CPP such as Tat that crosses the blood brain barrier will not share a cell entry pathway with a cell-specific CPP. Even for a particular CPP the mechanism of transduction likely varies depending on the specific cargo fused to it, with changes in parameters such as local milieu and pH almost certainly playing a part. This is further complicated by recent data suggesting that the local concentration of a CPP may influence the internalization pathway used [45][46][47]. It should be noted that elucidation of the mechanism of transduction is not only of theoretical interest as the loading of cargoes must be achieved in a way as to not interfere with either the binding or cell internalization mechanism of CPPs. For example changing the hydrophobicity, but not the cationic charge, of a guanidine-rich homo-polymer significantly changed its transduction abilities and ability to internalize cargoes [48].
Although the exact transduction mechanism of CPPs remains elusive, extensive work from multiple investigators has shed considerable light. There is evidence both for mechanisms that are non-endocytic/energy independent or endocytic/energy-dependent [49]. The broad range of cells that are readily transducible by non-specific CPPs such as Tat suggests a role for ubiquitously shared cellular structures such as surface binding to plasma membrane phospholipids or, in particular proteoglycans through electrostatic interactions, as a first step towards cell entry [50][51]. Cell lines deficient in heparan sulfate have significantly reduced transduction by cationic peptides [10][52][53]. This reduction suggests that electrostatic interactions on the cell surface, separate from CPP-lipid interactions, contribute to protein transduction. It is likely that transduction is a two-step process, with the first step being electrostatic interaction of non-specific CPPs with anionic elements, such as glycosaminoglycans on the cell surface that draw the CPPs into close proximity to the plasma membrane. Subsequently, cationic CPPs bearing small cargoes likely enter cells via direct translocation, with uptake of larger cargoes mediated by micropinocytosis, a more energy-dependent and slower process [54]. Transduction has been shown to occur at 4 °C and after depletion of the adenosine triphosphate (ATP) pool [10], albeit at a reduced level, suggesting that it is not exclusively an energy-dependent process. Research also suggests that increasing hydrophobic characteristics of a CPP, as in the case of Tat, increases its efficiency as a transporter [55].

5. Cell Penetrating Peptides as Gene Delivery Vectors

Although CPPs have been used as vectors for delivery of drugs [56][57][58][59], other peptides of therapeutic potential [60][61][62][63][64][65][66][67][68], proteins [64][69][70][71][72][73], radioisotopes [24][74][75][76], quantum dots [77][78] and photosensitizers [79][80], this entry will focus on use of CPPs as vectors for nucleic acid delivery, be they genes, oligonucleotides, peptide nucleic acid conjugates, small interfering RNA (siRNA) or the newest application with DNA origami. Although there is literature on all of these applications, most interest and work done to date has been with siRNA. The necessary factors to consider in these applications is the platform’s ability to successfully conjugate nucleic acids to CPPs, escape from enzymatic degradation in serum, escape the reticuloendothelial compartments, successfully cross cell membranes, escape from endocytic degradation and, in cases of gene delivery, achieve nuclear localization.

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics12030225

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