More Like this

1. Cell Penetrating Peptides, Novel Vectors for Gene Therapy

   https://doi.org/10.3390/pharmaceutics12030225  

   Taylor, Rebecca E.; Zahid, Maliha (March 2020, Pharmaceutics)

   null (Ed.)

   Cell penetrating peptides (CPPs), also known as protein transduction domains (PTDs), first identified ~25 years ago, are small, 6–30 amino acid long, synthetic, or naturally occurring peptides, able to carry variety of cargoes across the cellular membranes in an intact, functional form. Since their initial description and characterization, the field of cell penetrating peptides as vectors has exploded. The cargoes they can deliver range from other small peptides, full-length proteins, nucleic acids including RNA and DNA, liposomes, nanoparticles, and viral particles as well as radioisotopes and other fluorescent probes for imaging purposes. In this review, we will focus briefly on their history, classification system, and mechanism of transduction followed by a summary of the existing literature on use of CPPs as gene delivery vectors either in the form of modified viruses, plasmid DNA, small interfering RNA, oligonucleotides, full-length genes, DNA origami or peptide nucleic acids. 

   more » « less
2. Enhancing Antigen Presentation and Inducing Antigen-Specific Immune Tolerance with Amphiphilic Peptides

   https://doi.org/10.4049/jimmunol.1901301  

   Li, Meng; Itoh, Arata; Xi, Jingchao; Yu, Chunsong; Wu, Yuehong; Ridgway, William_M; Liu, Haipeng (October 2021, The Journal of Immunology)

   Abstract Ag-specific immunotherapy to restore immune tolerance to self-antigens, without global immune suppression, is a long-standing goal in the treatment of autoimmune disorders such as type 1 diabetes (T1D). However, vaccination with autoantigens such as insulin or glutamic acid decarboxylase have largely failed in human T1D trials. Induction and maintenance of peripheral tolerance by vaccination requires efficient autoantigen presentation by APCs. In this study, we show that a lipophilic modification at the N-terminal end of CD4+ epitopes (lipo-peptides) dramatically improves peptide Ag presentation. We designed amphiphilic lipo-peptides to efficiently target APCs in the lymph nodes by binding and trafficking with endogenous albumin. Additionally, we show that lipophilic modification anchors the peptide into the membranes of APCs, enabling a bivalent cell-surface Ag presentation. The s.c. injected lipo-peptide accumulates in the APCs in the lymph node, enhances the potency and duration of peptide Ag presentation by APCs, and induces Ag-specific immune tolerance that controls both T cell– and B cell–mediated immunity. Immunization with an amphiphilic insulin B chain 9–23 peptide, an immunodominant CD4+ T cell epitope in NOD mice, significantly suppresses the activation of T cells, increases inhibitory cytokine production, induces regulatory T cells, and delays the onset and lowers the incidence of T1D. Importantly, treatment with a lipophilic β-cell peptide mixture delays progression to end-stage diabetes in acutely diabetic NOD mice, whereas the same doses of standard soluble peptides were not effective. Amphiphilic modification effectively enhances Ag presentation for peptide-based immune regulation of autoimmune diseases. 

   more » « less
3. Temporary Membrane Permeabilization via the Pore-Forming Toxin Lysenin

   https://doi.org/10.3390/toxins12050343  

   Shrestha, Nisha; Thomas, Christopher A.; Richtsmeier, Devon; Bogard, Andrew; Hermann, Rebecca; Walker, Malyk; Abatchev, Gamid; Brown, Raquel J.; Fologea, Daniel (May 2020, Toxins)

   null (Ed.)

   Pore-forming toxins are alluring tools for delivering biologically-active, impermeable cargoes to intracellular environments by introducing large conductance pathways into cell membranes. However, the lack of regulation often leads to the dissipation of electrical and chemical gradients, which might significantly affect the viability of cells under scrutiny. To mitigate these problems, we explored the use of lysenin channels to reversibly control the barrier function of natural and artificial lipid membrane systems by controlling the lysenin’s transport properties. We employed artificial membranes and electrophysiology measurements in order to identify the influence of labels and media on the lysenin channel’s conductance. Two cell culture models: Jurkat cells in suspension and adherent ATDC5 cells were utilized to demonstrate that lysenin channels may provide temporary cytosol access to membrane non-permeant propidium iodide and phalloidin. Permeability and cell viability were assessed by fluorescence spectroscopy and microscopy. Membrane resealing by chitosan or specific media addition proved to be an effective way of maintaining cellular viability. In addition, we loaded non-permeant dyes into liposomes via lysenin channels by controlling their conducting state with multivalent metal cations. The improved control over membrane permeability might prove fruitful for a large variety of biological or biomedical applications that require only temporary, non-destructive access to the inner environment enclosed by natural and artificial membranes. 

   more » « less
4. Near‐Infrared Light Triggered‐Release in Deep Brain Regions Using Ultra‐photosensitive Nanovesicles

   https://doi.org/10.1002/ange.201915296  

   Xiong, Hejian; Li, Xiuying; Kang, Peiyuan; Perish, John; Neuhaus, Frederik; Ploski, Jonathan E.; Kroener, Sven; Ogunyankin, Maria O.; Shin, Jeong Eun; Zasadzinski, Joseph A.; et al (March 2020, Angewandte Chemie)

   Abstract Remote and minimally‐invasive modulation of biological systems with light has transformed modern biology and neuroscience. However, light absorption and scattering significantly prevents penetration to deep brain regions. Herein, we describe the use of gold‐coated mechanoresponsive nanovesicles, which consist of liposomes made from the artificial phospholipid Rad‐PC‐Rad as a tool for the delivery of bioactive molecules into brain tissue. Near‐infrared picosecond laser pulses activated the gold‐coating on the surface of nanovesicles, creating nanomechanical stress and leading to near‐complete vesicle cargo release in sub‐seconds. Compared to natural phospholipid liposomes, the photo‐release was possible at 40 times lower laser energy. This high photosensitivity enables photorelease of molecules down to a depth of 4 mm in mouse brain. This promising tool provides a versatile platform to optically release functional molecules to modulate brain circuits. 

   more » « less
5. Antibiotic–cell‐penetrating peptide conjugates targeting challenging drug‐resistant and intracellular pathogenic bacteria

   https://doi.org/10.1111/cbdd.13930  

   Zeiders, Samantha M.; Chmielewski, Jean (August 2021, Chemical Biology & Drug Design)

   Abstract The failure to treat everyday bacterial infections is a current threat as pathogens are finding new ways to thwart antibiotics through mechanisms of resistance and intracellular refuge, thus rendering current antibiotic strategies ineffective. Cell‐penetrating peptides (CPPs) are providing a means to improve antibiotics that are already approved for use. Through coadministration and conjugation of antibiotics with CPPs, improved accumulation and selectivity with alternative and/or additional modes of action against infections have been observed. Herein, we review the recent progress of this antibiotic–cell‐penetrating peptide strategy in combatting sensitive and drug‐resistant pathogens. We take a closer look into the specific antibiotics that have been enhanced, and in some cases repurposed as broad‐spectrum drugs. Through the addition and conjugation of cell‐penetrating peptides to antibiotics, increased permeation across mammalian and/or bacterial membranes and a broader range in bacterial selectivity have been achieved. 

   more » « less