Cell-Penetrating Peptides: From Basic Research to Clinics

Many human pathologies present unmet medical needs because of the presence of cell and tissue barriers that prevent therapeutics from reaching their specific intracellular targets. Conjugating therapeutics with peptidic delivery factors, particularly cell-penetrating peptides (CPPs), could enhance their cellular internalization and therapeutic efficacy. Medical application of CPPs has been considered for the delivery of various types of therapeutic molecules, such as antimicrobial, anti-inflammatory, antineoplastic, and neuroprotective agents. Since their discovery, numerous preclinical evaluations have been performed in animal models to investigate applications of CPP-derived therapeutics. Some of these peptides have entered into Phase I, Phase II, and, in some cases, Phase III clinical trials. The presence of cell and tissue barriers together with the low biomembrane permeability of various therapeutics often hampers systemic drug distribution; thus, most of the available molecules are of limited therapeutic value. Opportunities to increase medicament concentrations in areas that are difficult to access now exist with the advent of cell-penetrating peptides (CPPs), which can transport into the cell a wide variety of biologically active conjugates (cargoes). Numerous preclinical evaluations with CPP-derived therapeutics have provided promising results in various disease models that, in some cases, prompted clinical trials. The outcome of these investigations has thus opened new perspectives for CPP application in the development of unprecedented human therapies that are well tolerated and directed to intracellular targets. The presence of cell and tissue barriers together with the low biomembrane permeability of various therapeutics often hampers systemic drug distribution; thus, most of the available molecules are of limited therapeutic value. Opportunities to increase medicament concentrations in areas that are difficult to access now exist with the advent of cell-penetrating peptides (CPPs), which can transport into the cell a wide variety of biologically active conjugates (cargoes). Numerous preclinical evaluations with CPP-derived therapeutics have provided promising results in various disease models that, in some cases, prompted clinical trials. The outcome of these investigations has thus opened new perspectives for CPP application in the development of unprecedented human therapies that are well tolerated and directed to intracellular targets. peptides comprising a polycationic CPP and a neutralizing polyanion separated by a protease cleavable linker. dynamic interface that separates the brain parenchyma from the vasculature protecting the CNS from potential external damage and regulating the transport of essential molecules to maintain a stable environment. short peptides able to pass through tissue and cell membranes via energy-dependent or -independent mechanisms; used to transport into cells a wide variety of biologically active conjugates (cargoes). various mechanisms for the transport of molecules into cells. deleterious effects – such as formation of oxygen free radicals, calcium overload, and neutrophil-mediated myocardial and endothelial injury – induced by reperfusion therapy following ischemia. blockage of middle cerebral artery that causes oxygen deprivation in brain tissue; commonly used to create an animal model of ischemia or hypoxia. multifunctional transcription factor that controls the expression of several proinflammatory and stress response mediators. selective inhibitor peptide of NF-κB; blocks the interaction of NEMO with the IκB kinase complex, preventing NF-κB activation. short sequence of positively charged amino acids that mediates the nuclear import of proteins by binding to its receptors, known as importins. synthetic homologs of nucleic acids in which the phosphate–sugar polynucleotide backbone is replaced by a flexible pseudopeptide polymer to which the nucleobases are linked. non-surgical procedure, commonly known as coronary angioplasty, used to treat stenotic coronary arteries of the heart. synthetic DNA analogs that inhibit gene expression in a sequence-dependent manner. class of double-stranded RNA molecules that mediate gene silencing by degradation/blockage of translation of the target mRNA.