ReviewsOn The Biomedical Promise of Cell Penetrating Peptides: Limits Versus Prospects
Section snippets
INTRODUCTION
The full therapeutic potential of peptide‐, protein‐, and nucleic acid‐based drugs is frequently compromised by their limited ability to cross the plasma membrane of mammalian cells, resulting in poor cellular access and inadequate therapeutic efficacy.1, 2 Today this hurdle represents a major challenge for the biomedical development and commercial success of many biopharmaceuticals. Over the past decade, however, attractive prospects for a substantial improvement in the cellular delivery of
Successful Delivery by the CPP Approach
The following section covers selected examples of successful drug (or model drug) delivery by the CPP approach. In particular, we focus on distinct in vivo studies, whereas a broader outline is given in the review of Dietz and Bdeltahr.8 A pioneering piece of work on CPP mediated cellular delivery of heterologous proteins was authored by Fawell et al.53 The authors covalently linked Tat peptides to β‐galactosidase, horseradish peroxidase, RNase A, and domain III of Pseudomonas exotoxin A.
Metabolic Degradation
A major obstacle to CPP mediated drug delivery is thought to consist in the often rapid metabolic clearance of the peptides when in contact or passing the enzymatic barriers of epithelia and endothelia. Koppelhus et al.,103 for example, reported that the observed poor intracellular uptake of CPPs might results from quick degradation of the fluorescence labeled CPPs in the cells. Until today, however, despite its general relevance, information on the momentous subject of enzymatic stability and
NEW PERSPECTIVES FOR APPLICATION OF CPPs IN DRUG DELIVERY
As a consequence of the described limitations of CPP mediated translocation, for example, the dependence on the state of cellular differentiation, we aim in this final section at the identification of promising niches for CPP application in drug delivery. Ideally, these approaches should either overcome or bypass the given limitations of CPP mediated drug delivery described above and, thus, offer a realistic avenue toward the usage of CPPs in a therapeutic context. As inspired by current
CONCLUSION
Over more than a decade, a broad variety of CPPs has been evaluated for their capacity to support the cellular delivery of therapeutics that normally do not cross the plasma membrane. Although a number of landmark studies in the field claimed a practically unrestricted cellular access of CPPs and CPP associated cargos, crucial limitations to these shuttles have been pointed out more recently. In this review, we attempted to review distinct aspects of CPP mediated cellular delivery. Besides the
REFERENCES (168)
- et al.
Nucleic acid therapeutics: State of the art and future prospects
Blood
(1998) - et al.
The third helix of the Antennapedia homeodomain translocates through biological membranes
J Biol Chem
(1994) - et al.
A truncated HIV‐1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus
J Biol Chem
(1997) - et al.
In vivo protein transduction: Intracellular delivery of biologically active proteins, compounds and DNA
Trends Pharmacol Sci
(2000) - et al.
Delivery of bioactive molecules into the cell: The Trojan horse approach
Mol Cell Neurosci
(2004) - et al.
Design of carrier peptide‐oligonucleotide conjugates with rapid membrane translocation and nuclear localization properties
Biochem Biophys Res Commun
(1998) - et al.
Mechanism of action of the antimicrobial peptide buforin II: Buforin II kills microorganisms by penetrating the cell membrane and inhibiting cellular functions
Biochem Biophys Res Commun
(1998) - et al.
Amino acid sequences of two proline‐rich bactenecins. Antimicrobial peptides of bovine neutrophils
J Biol Chem
(1990) - et al.
Membrane channel formation by antimicrobial protegrins
Biochim Biophys Acta
(1999) - et al.
VE‐cadherin‐derived cell‐penetrating peptide, pVEC, with carrier functions
Exp Cell Res
(2001)
Intercellular trafficking of adenovirus‐delivered HSV VP22 from the retinal pigment epithelium to the photoreceptors‐implications for gene therapy
Mol Ther
Particle formation by a conserved domain of the herpes simplex virus protein VP22 facilitating protein and nucleic acid delivery
J Biol Chem
In vitro gene delivery by a novel human calcitonin (hCT)‐derived carrier peptide
Bioorg Med Chem Lett
Mammary epithelial cell‐cycle progression via the alpha(2)beta(1) integrin: Unique and synergistic roles of the alpha(2) cytoplasmic domain
Am J Pathol
Antisense inhibition of P‐glycoprotein expression using peptide‐oligonucleotide conjugates
Biochem Pharmacol
Complexes of plasmid DNA with basic domain 47–57of the HIV‐1 Tat protein are transferred to mammalian cells by endocytosis‐mediated pathways
J Biol Chem
Oligomers of the arginine‐rich motif of the HIV‐1 TAT protein are capable of transferring plasmid DNA into cells
J Biol Chem
Novel branching membrane translocational peptide as gene delivery vector
Bioorg Med Chem
The use of cell‐penetrating peptides as a tool for gene regulation
Drug Discov Today
Cellular uptake of the tat protein from human immunodeficiency virus
Cell
Protein transduction: Unrestricted delivery into all cells?
Trends Cell Biol
Arginine‐rich peptides: Potential for intracellular delivery of macromolecules and the mystery of the translocation mechanisms
Int J Pharm
Arginine‐rich peptides. An abundant source of membrane‐permeable peptides having potential as carriers for intracellular protein delivery
J Biol Chem
Cell internalization of the third helix of the Antennapedia homeodomain is receptor‐independent
J Biol Chem
Three‐dimensional structure of the tetragonal crystal form of egg‐white avidin in its functional complex with biotin at 2.7 A resolution
J Mol Biol
On the mechanism of non‐endosomial peptide‐mediated cellular delivery of nucleic acids
Biochim Biophys Acta
Translocation of analogues of the antimicrobial peptides magainin and buforin across human cell membranes
J Biol Chem
Bilayer interaction and localization of cell penetrating peptides with model membranes: A comparative study of a human calcitonin (hCT)‐derived peptide with pVEC and pAntp (43–58)
Biochim Biophys Acta
Calcitonin
Am J Med Sci
Cell‐penetrating peptides. A reevaluation of the mechanism of cellular uptake
J Biol Chem
Studies on the internalization mechanism of cationic cell‐penetrating peptides
J Biol Chem
Antennapedia and HIV transactivator of transcription (TAT) “protein transduction domains” promote endocytosis of high molecular weight cargo upon binding to cell surface glycosaminoglycans
J Biol Chem
Cytosolic delivery of a p16‐peptide oligoarginine conjugate for inhibiting proliferation of MCF7 cells
J Control Release
Transmembrane delivery of protein and peptide drugs by TAT‐mediated transduction in the treatment of cancer
Adv Drug Deliv Rev
A stepwise dissection of the intracellular fate of cationic cell‐penetrating peptides
J Biol Chem
Antisense pharmacodynamics: Critical issues in the transport and delivery of antisense oligonucleotides
Pharm Res
In vivo protein transduction: Delivery of a biologically active protein into the mouse
Science
Cell penetration by transportan
FASEB J
Cell‐penetrating peptides: Small from inception to application
Q Rev Biophys
New advances in the transport of doxorubicin through the blood‐brain barrier by a peptide vector‐mediated strategy
Mol Pharmacol
Rapid membrane permeabilization and inhibition of vital functions of gram‐negative bacteria by bactenecins
Infect Immun
In vitro uptake and stability study of pVEC and its all‐D analog
Biol Chem
Intercellular trafficking of VP22‐GFP fusion proteins
Gene Ther
Cellular internalization of enhanced green fluorescent protein ligated to a human calcitonin‐based carrier peptide
Chem Biochem
Cellular internalization of human calcitonin derived peptides in MDCK monolayers: A comparative study with Tat(47–57) and penetratin (43–58)
Pharm Res
Translocation of human calcitonin in respiratory nasal epithelium is associated with self‐assembly in lipid membrane
Biochemistry
Peptide dendrimers based on polyproline helices
J Am Chem Soc
Potential peptide carriers: Amphipathic proline‐rich peptides derived from the N‐terminal domain of gamma‐zein
Angew Chem Int Ed Engl
Amphipathic peptides and drug delivery
Biopolymers
A peptide inhibitor of c‐Jun N‐terminal kinase protects against excitotoxicity and cerebral ischemia
Nat Med
Cited by (139)
Multiscale modeling of the cellular uptake of C6 peptide-siRNA complexes
2022, Computational Biology and ChemistryCitation Excerpt :Due to the limitations of small molecule drugs, larger molecules such as nucleic acids, peptides, and proteins have been developed as therapeutics over the past few decades (Brasseur and Divita, 1798; Heitz et al., 2009; Foerg and Merkle, 2008).
Antimicrobial synergy between mRNA targeted peptide nucleic acid and antibiotics in E. coli
2018, Bioorganic and Medicinal Chemistry LettersCell penetrating peptides in ocular drug delivery: State of the art
2018, Journal of Controlled ReleaseIntracellular Delivery via Noncharged Sequence-Defined Cell-Penetrating Oligomers
2018, Bioconjugate ChemistryCell targeting peptides as smart ligands for targeting of therapeutic or diagnostic agents: a systematic review
2017, Colloids and Surfaces B: BiointerfacesSAP(E) - A cell-penetrating polyproline helix at lipid interfaces
2016, Biochimica et Biophysica Acta - Biomembranes
The authors are pleased to dedicate this review to Professor William I. Higuchi PhD, Salt Lake City, in recognition of his pioneering contributions to fundamental pharmaceutical research.