Efficient intracellular drug delivery and target specificity are often hampered by the presence of biological barriers. Thus, compounds that efficiently cross cell membranes are the key to improving ...the therapeutic value and on-target specificity of non-permeable drugs. The discovery of cell-penetrating peptides (CPPs) and the early design approaches through mimicking the natural penetration domains used by viruses have led to greater efficiency of intracellular delivery. Following these nature-inspired examples, a number of rationally designed CPPs has been developed. In this review, a variety of CPP designs will be described, including linear and flexible, positively charged and often amphipathic CPPs, and more rigid versions comprising cyclic, stapled, or dimeric and/or multivalent, self-assembled peptides or peptido-mimetics. The application of distinct design strategies to known physico-chemical properties of CPPs offers the opportunity to improve their penetration efficiency and/or internalization kinetics. This led to increased design complexity of new CPPs that does not always result in greater CPP activity. Therefore, the transition of CPPs to a clinical setting remains a challenge also due to the concomitant involvement of various internalization routes and heterogeneity of cells used in the in vitro studies.
Protein-protein interactions (PPIs) have emerged as important and challenging targets in chemical biology and medicinal chemistry. The main difficulty encountered in the discovery of small molecule ...modulators derives from the large contact surfaces involved in PPIs when compared with those that participate in protein-small molecule interactions. Because of their intrinsic features, peptides can explore larger surfaces and therefore represent a useful alternative to modulate PPIs. The use of peptides as therapeutics has been held back by their instability in vivo and poor cell internalization. However, more than 200 peptide drugs and homologous compounds (proteins or antibodies) containing peptide bonds are (or have been) on the market, and many alternatives are now available to tackle these limitations. This review will focus on the latest progress in the field, spanning from "lead" identification methods to binding evaluation techniques, through an update of the most successful examples described in the literature.
While knowledge of the composition and mode of action of bee and wasp venoms dates back 50 years, the therapeutic value of these toxins remains relatively unexploded. The properties of these venoms ...are now being studied with the aim to design and develop new therapeutic drugs. Far from evaluating the extensive number of monographs, journals and books related to bee and wasp venoms and the therapeutic effect of these toxins in numerous diseases, the following review focuses on the three most characterized peptides, namely melittin, apamin, and mastoparan. Here, we update information related to these compounds from the perspective of applied science and discuss their potential therapeutic and biotechnological applications in biomedicine.
Brain delivery is one of the major challenges in drug development because of the high number of patients suffering from neural diseases and the low efficiency of the treatments available. Although ...the blood-brain barrier (BBB) prevents most drugs from reaching their targets, molecular vectors - known as BBB shuttles - offer great promise to safely overcome this formidable obstacle. In recent years, peptide shuttles have received growing attention because of their lower cost, reduced immunogenicity, and higher chemical versatility than traditional Trojan horse antibodies and other proteins.
A Third Shot at EGFR: New Opportunities in Cancer Therapy Guardiola, Salvador; Varese, Monica; Sánchez-Navarro, Macarena ...
Trends in pharmacological sciences (Regular ed.),
December 2019, 2019-12-00, 20191201, Letnik:
40, Številka:
12
Journal Article
Recenzirano
Epidermal growth factor receptor (EGFR) inhibitors were among the first type of targeted agents discovered in cancer and currently constitute the standard of care for a wide range of lung and colon ...malignancies. However, the therapeutic progress achieved with these drugs has been accompanied by the identification of an ever-increasing number of acquired resistance mechanisms that inevitably appear in nearly all patients. Increased knowledge on EGFR biochemistry, cellular crosstalk, and resistance pathways provides an opportunity to establish effective combination therapies and discover novel-acting inhibitors that prevent or overcome therapeutic resistance. One such strategy is the selective blockade of circulating growth factors such as EGF. In this review, we address the uses and limitations of approved EGFR inhibitors and explore the potential of drug combinations and new third avenues to block the activation of the EGFR.
The initial excitement over the efficacy of EGFR-targeted drugs (TKIs and mAbs) has been offset by a growing number of drug-resistant mutations that invariably appear in patients; thus novel-acting drugs and synergistic combinations are in high demand.The direct inhibition of the main activating ligand (EGF) is considered a promising strategy and has been explored with other kinase receptors, such as VEGF, FGF, and TGF-β.EGF is a small protein with no active sites and/or binding cavities that can be efficiently drugged using traditional small-molecule approaches and has thus remained a challenging target.Peptides, vaccines, and single-chain antibodies against EGF have recently emerged as a new class of biotherapeutics in the fight against EGFR-driven tumours.
Proline-rich peptides are a chemically and structurally diverse family of cell-penetrating vectors characterised by the presence of pyrrolidine rings from prolines. Amphipathic Pro-rich peptides are ...particularly effective, demonstrating efficient cellular uptake and non-cytotoxicity. Derivatives with hydrophobic moieties, such as fatty acids or silaproline, have shown highly improved internalisation efficiency; an all D-amino acid version of the CPP SAP was shown to be completely protease resistant and was evaluated in a preliminary
in vivo study. CD and TEM studies regarding the self-assembly properties of this family of peptides highlight the possible role of aggregated species in the internalisation process. Finally, these CPPs were shown to be internalised via caveolae or lipid-rafts mediated endocytosis, which circumvents the lysosomal route of degradation.
Cell‐penetrating peptides (CPPs) are powerful tools to transport cell‐impermeable cargoes into the cytoplasm without damaging the cell membrane. The vast majority of these peptides described to date ...share several features, among others, they are positively charged at physiological pH. In several cases a clear correlation between an increasing number of positive charges and internalization properties has been reported. Here, we describe what, to the best of our knowledge, is the first anionic CPP. This new compound SAP(E) internalizes into a range of cell lines with good efficiency and it shows low toxicity. We also report on the internalization mechanism. The discovery of this new class of CPP opens the way to the intracellular delivery of new molecular cargoes.
A SAP delivery: SAP(E) is an amphipathic proline‐rich peptide derived from sweet arrow peptide (SAP) and adopts a defined PPII secondary structure in solution. Despite its overall negative charge it can be internalized into different cell lines without toxicity (see scheme). By making use of the noncationic nature of SAP(E) intracellular delivery of new cargoes might be possible.
The blood–brain barrier (BBB) limits the delivery of therapeutics to the brain but also represents the main gate for nutrient entrance. Targeting the natural transport mechanisms of the BBB offers an ...attractive route for brain drug delivery. Peptide shuttles are able to use these mechanisms to increase the transport of compounds that cannot cross the BBB unaided. As peptides are a group of biomolecules with unique physicochemical and structural properties, the field of peptide shuttles has substantially evolved in the last few years. In this review, we analyze the main classifications of BBB–peptide shuttles and the leading sources used to discover them.
The electronic spin filtering capability of a single chiral helical peptide is measured. A ferromagnetic electrode source is employed to inject spin‐polarized electrons in an asymmetric ...single‐molecule junction bridging an α‐helical peptide sequence of known chirality. The conductance comparison between both isomers allows the direct determination of the polarization power of an individual chiral molecule.
Shuttle-Mediated Drug Delivery to the Brain Malakoutikhah, Morteza; Teixidó, Meritxell; Giralt, Ernest
Angewandte Chemie (International ed.),
August 22, 2011, Letnik:
50, Številka:
35
Journal Article
Recenzirano
Advances in the field of shuttle‐mediated drug delivery have been made in the last decade; however, the treatment of brain disorders still remains a great challenge because of the presence of the ...blood–brain barrier (BBB), a structure that limits the access of drugs to their site of action in the central nervous system. Several strategies have been proposed to enhance the transport of drugs across the BBB. In this Review, we focus on the vector‐mediated approach, in which a drug is coupled to a molecule (shuttle) that has the ability to cross the BBB and deliver the drug to the brain.
Operating a shuttle service: The use of chemical shuttles to deliver drugs to the brain is a plausible solution to overcome the obstacle posed by the blood–brain barrier. The drug is conjugated to a shuttle molecule that has the ability to permeate the blood–brain barrier (see picture).
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