Cell-Penetrating Proline-Rich Peptidomimetics

Barcelona Biomedical Research Institute, University of Barcelona, Spain.
Methods in Molecular Biology (Impact Factor: 1.29). 02/2007; 386(51):241-67. DOI: 10.1007/978-1-59745-430-8_9
Source: PubMed


Cell-penetrating peptides (CPPs) offer potential as delivery agents for the cellular administration of drugs. However, the pharmacological utility of CPPs that are derived from natural amino acids is limited by their rapid metabolic degradation, low membrane permeability, and toxicity. Various peptidomimetics able to overcome these problems have been described, including peptides formed by D-amino acids and beta-peptides. This chapter summarizes the synthesis of gamma-proline-derived peptides and polyproline dendrimers for drug delivery applications, and includes descriptions of several modifications in the gamma-peptides (mimicking the side chains of the alpha-amino acids) or modulating the dendrimer surface. 5(6)-Carboxyfluorescein labeling of the aforementioned peptidomimetics for use in cell translocation studies is also described. Furthermore, different protocols for the study of the drug delivery capabilities of these compounds are reviewed, including enzymatic stability studies, cellular uptake measurements by plate fluorimetry and flow cytometry, confocal laser scanning microscopy, and cytotoxicity assays.

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    ABSTRACT: The recent discovery of new potent therapeutic molecules that do not reach the clinic due to poor delivery and low bioavailability have made of delivery a key stone in therapeutic development. Several technologies have been designed to improve cellular uptake of therapeutic molecules, including cell-penetrating peptides (CPPs). CPPs were first discovered based on the potency of several proteins to enter cells. Numerous CPPs have been described so far, which can be grouped into two major classes, the first requiring chemical linkage with the drug for cellular internalization and the second involving formation of stable, non-covalent complexes with drugs. Nowadays, CPPs constitute very promising tools for non-invasive cellular import of cargo and have been successfully applied for in vitro and in vivo delivery of therapeutic molecules varying from small chemical molecule, nucleic acids, proteins, peptides, liposomes and particles. This review will focus on the structure/function and cellular uptake mechanism of CPPs in the general context of drug delivery. We will also highlight the application of peptide carriers for the delivery of therapeutic molecules and provide an update of their clinical evaluation.
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    ABSTRACT: The intrinsic property of cell-penetrating peptides (CPPs) to deliver therapeutic molecules (nucleic acids, drugs, imaging agents) to cells and tissues in a non-toxic manner, has pointed them as potential components of future drugs and disease diagnostic agents. These versatile peptides are simple to synthesize, functionalize, and characterize yet are able to deliver covalently or non-covalently conjugated bioactive cargos (from small chemical drugs to large plasmid DNA) inside cells, primarily via endocytosis, in order to obtain high levels of gene expression, gene silencing or tumor targeting. Tipically CPPs are often passive and non-selective, yet must must be functionalized or chemically modified to create effective delivery vectors that succeed in targeting specific cells or tissues. Furthermore, the design of clinically effective systemic delivery systems requires the same amount of attention to detail in both design of the delivered cargo and the cell penetrating peptide used to deliver it.
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