Cell-penetrating peptides transport therapeutics into cells

Abstract

Nearly 30years ago, certain small, relatively nontoxic peptides were discovered to be capable of traversing the cell membrane. These cell-penetrating peptides, as they are now called, have been shown to not only be capable of crossing the cell membrane themselves but can also carry many different therapeutic agents into cells, including small molecules, plasmid DNA, siRNA, therapeutic proteins, viruses, imaging agents, and other various nanoparticles. Many cell-penetrating peptides have been derived from natural proteins, but several other cell-penetrating peptides have been developed that are either chimeric or completely synthetic. How cell-penetrating peptides are internalized into cells has been a topic of debate, with some peptides seemingly entering cells through an endocytic mechanism and others by directly penetrating the cell membrane. Although the entry mechanism is still not entirely understood, it seems to be dependent on the peptide type, the peptide concentration, the cargo the peptide transports, and the cell type tested. With new intracellular disease targets being discovered, cell-penetrating peptides offer an exciting approach for delivering drugs to these intracellular targets. There are hundreds of cell-penetrating peptides being studied for drug delivery, and ongoing studies are demonstrating their success both in vitro and in vivo.

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

“…This phenotype resembles vesicle entrapment and suggests endosomal compartmentalization (53,54). In HBMEC, the CPP-FITC 34 -51 ), the second ␣-helix, ␣2H (YopM [53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71] ), and both ␣-helices, 2␣H (YopM ). The 3D structure was generated using PyMOL.…”

“…It is known that CPPs can utilize different entry routes simultaneously and that their uptake depends on many factors, such as the delivered cargo, physicochemical characteristics of the peptides, and, no less important, the particular experimental conditions (67). For Tat, several endocytic routes have been proposed, such as macropinocytosis (68), clathrin-mediated endocytosis (69), and caveola-mediated endocytosis (70).…”

Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-β signaling

“…Peptides as drugs have advantages as well as disadvantages compared with other small molecules (37,57). Most importantly, peptides can be designed to bind with high specificity to their in vivo targets and have relatively few off-target side effects.…”

“…Most importantly, peptides can be designed to bind with high specificity to their in vivo targets and have relatively few off-target side effects. While the market for peptide-based drugs is currently estimated at more than 40 billion per year (57), a major limiting factor is the permeability barrier imposed by the plasma membrane (36)(37)(38). To overcome that limitation, over 100 peptide sequences have been identified capable of transporting bioactive molecules (38,58).…”

“…Thus, for some conditions, the aforementioned global approaches may be unwarranted and a strategy that specifically targets the causal pathway or pathways more efficacious. In the current study, we do just that by using a cell-penetrating peptide (CPP) (36)(37)(38) consisting of the HIV TAT protein fused to an N-terminal 31-amino acid SNX9 fragment found to bind and specifically inhibit pSMAD3 nuclear import and biologic action. The results show that, while this TAT-SNX9 peptide had no effect on TGF-β signaling mediated via pSMAD2 or luciferase activity stimulated by bone morphogenetic protein 4 (BMP4), EGF, or PDGF, it inhibited (a) TGF-β induction of pSMAD3 target genes, soft agar TGF-β is considered a master switch in the pathogenesis of organ fibrosis.…”