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Developing highly active, multivalent ligands as therapeutic agents is challenging because of delivery issues, limited cell permeability, and toxicity. Here, we report intrinsically cell-penetrating multivalent ligands that target the trinucleotide repeat DNA and RNA in myotonic dystrophy type 1 (DM1), interrupting the disease progression in two ways. The oligomeric ligands are designed based on the repetitive structure of the target with recognition moieties alternating with bisamidinium groove binders to provide an amphiphilic and polycationic structure, mimicking cell-penetrating peptides. Multiple biological studies suggested the success of our multivalency strategy. The designed oligomers maintained cell permeability and exhibited no apparent toxicity both in cells and in mice at working concentrations. Furthermore, the oligomers showed important activities in DM1 cells and in a DM1 liver mouse model, reducing or eliminating prominent DM1 features. Phenotypic recovery of the climbing defect in adult DM1 Drosophila was also observed. This design strategy should be applicable to other repeat expansion diseases and more generally to DNA/RNA-targeted therapeutics.

Mycobacterium tuberculosis mannose-capped lipoarabinomannan inhibits the release of proinflammatory cytokines by LPS-stimulated human dendritic cells (DCs) via targeting the C-type lectin receptor DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN). With the aim of mimicking the bioactive supramolecular structure of mannose-capped lipoarabinomannan, we designed and synthesized a set of poly(phosphorhydrazone) dendrimers grafted with mannose units, called mannodendrimers, that differed by size and the number and length of their (α1→2)-oligommanoside caps. A third-generation dendrimer bearing 48 trimannoside caps (3T) and a fourth-generation dendrimer bearing 96 dimannosides (4D) displayed the highest binding avidity for DC-SIGN. Moreover, these dendrimers inhibited proinflammatory cytokines, including TNF-α, production by LPS-stimulated DCs in a DC-SIGN–dependent fashion. Finally, in a model of acute lung inflammation in which mice were exposed to aerosolized LPS, per os administration of 3T mannodendrimer was found to significantly reduce neutrophil influx via targeting the DC-SIGN murine homolog SIGN-related 1. The 3T mannodendrimer therefore represents an innovative fully synthetic compound for the treatment of lung inflammatory diseases.

MicroRNAs (miRNAs) are short non-coding RNA molecules acting as gene regulators by repressing translation or by inducing degradation of the target RNA transcripts. Altered expression of miRNAs may be involved in the pathogenesis of many severe human diseases, opening new avenues in the field of therapeutic strategies, i.e., miRNA targeting or miRNA mimicking. In this context, the efficient and non-toxic delivery of premiRNA and antimiRNA molecules might be of great interest. The aim of the present paper is to determine whether an argininocalix[4]arene is able to efficiently deliver miRNA, premiRNA, and antimiRNA molecules to target cells, preserving their biological activity. This study points out that (1) the toxicity of argininocalix[4]arene 1 is low, and it can be proposed for long-term treatment of target cells, being that this feature is a pre-requisite for the development of therapeutic protocols; (2) the delivery of premiRNA and antimiRNA molecules is efficient, being higher when compared with reference gold standards available; and (3) the biological activity of the premiRNAs and antimiRNAs is maintained. This was demonstrated using the argininocalix[4]arene 1 in miRNA therapeutic approaches performed on three well-described experimental model systems: (1) the induction of apoptosis by antimiR-221 in glioma U251 cells; (2) the induction of apoptosis by premiR-124 in U251 cells; and (3) the inhibition of pro-inflammatory IL-8 and IL-6 genes in cystic fibrosis IB3-1 cells. Our results demonstrate that the argininocalix[4]arene 1 should be considered a very useful delivery system for efficient transfer to target cells of both premiRNA and antimiRNA molecules, preserving their biological activity.

The relative content of NR2 subunits in the NMDA receptor confers specific signaling properties and plasticity to synapses. However, the mechanisms that dynamically govern the retention of synaptic NMDARs, in particular 2A-NMDARs, remain poorly understood. Here, we investigate the dynamic interaction between NR2 C termini and proteins containing PSD-95/Discs-large/ZO-1 homology (PDZ) scaffold proteins at the single molecule level by using high-resolution imaging. We report that a biomimetic divalent competing ligand, mimicking the last 15 amino acids of NR2A C terminus, specifically and efficiently disrupts the interaction between 2A-NMDARs, but not 2B-NMDARs, and PDZ proteins on the time scale of minutes. Furthermore, displacing 2A-NMDARs out of synapses lead to a compensatory increase in synaptic NR2B-NMDARs, providing functional evidence that the anchoring mechanism of 2A- or 2B-NMDARs is different. These data reveal an unexpected role of the NR2 subunit divalent arrangement in providing specific anchoring within synapses, highlighting the need to study such dynamic interactions in native conditions.

The interaction of exosomes (cell-secreted ∼ 100 nm-sized extracellular vesicles) or membrane-enveloped virions with cellular lipid membranes is often mediated by relatively weak ligand-receptor bonds. Interactions of this type can be studied using vesicles and observing their attachment to receptors located in a lipid bilayer formed at a solid surface. The contact region between a vesicle and the supported lipid bilayer and accordingly the number of ligand-receptor pairs there can be increased by deforming a vesicle. Herein, I (i) estimate theoretically the corresponding deformation energy assuming a disk-like or elongated shape of vesicles, (ii) present the equations allowing one to track such deformations by employing total internal reflection fluorescence microscopy and surface plasmon resonance, and (iii) briefly discuss some related experimental studies.

Here, the controlled formation of platinum nanoparticles (PtNPs) and silver nanoparticles (AgNPs) using amine-functionalized multivalent ligands are reported. The effects of reaction temperature and ligand multivalency on the growth kinetics, size, and shape of PtNPs and AgNPs were systematically studied by performing a stepwise and a one-step process. PtNPs and AgNPs were prepared in the presence of amine ligands using platinum (II) acetylacetonate and silver (I) acetylacetonate, respectively. The effects of ligands and temperature on the formation of PtNPs were studied using a transmission electron microscope (TEM). For the characterization of AgNPs, additionally, ultraviolet-visible (UV-Vis) absorption was employed. The TEM measurements revealed that PtNPs prepared at different temperatures (160–200 °C, in a stepwise process) are monodispersed and of spherical shape regardless of the ligand multivalency or reaction temperature. In the preparation of PtNPs by the one-step process, ligands affect the shape of the PtNPs, which can be explained by the affinity of the ligands. The TEM and UV-Vis absorption studies on the formation of AgNPs with mono-, di-, and trivalent ligands showed narrower size distributions, while increasing the temperature from 80 °C to 120 °C and with a trivalent ligand in a one-step process.

To design a theranostic capsule using the virus-like nanoparticle of the hepatitis E virus modified to display breast cancer cell targeting functional group (LXY30). Five surface-exposed residues were mutated to cysteine to allow conjugation to maleimide-linked chemical groups via thiol-selective linkages. Engineered virus-like nanoparticles were then covalently conjugated to a breast cancer recognized ligand, LXY30 and an amine-coupled near-infrared fluorescence dye. LXY30-HEV VLP was checked for its binding and entry to a breast cancer cell line and for tumor targeting to breast cancer tissue in mice. The engineered virus-like nanoparticle not only targeted cancer cells, but also appeared immune silent to native hepatitis E virus antibodies due to epitope disruption at the antibody-binding site. These results demonstrate the production of a theranostic capsule suitable for cancer diagnostics and therapeutics based on surface modification of a highly stable virus-like nanoparticle.

Radiopharmaceuticals are an integral component of nuclear medicine and are widely applied in diagnostics and therapy. Though widely applied, the development of an \"ideal\" radiopharmaceutical can be challenging. Issues such as specificity, selectivity, sensitivity, and feasible chemistry challenge the design and synthesis of radiopharmaceuticals. Over time, strategies to address the issues have evolved by making use of new technological advances in the fields of biology and chemistry. This review presents the application of few advances in design and synthesis of radiopharmaceuticals. The topics covered are bivalent ligand approach and lipidization as part of design modifications for enhanced selectivity and sensitivity and novel synthetic strategies for optimized chemistry and radiolabeling of radiopharmaceuticals.

The plethora of information about the expression of cancer cell-associated gangliosides, their role(s) in signal transduction, and their potential usefulness in the development of cancer treatments makes this an appropriate time to review these enigmatic glycosphingolipids. Evidence, reflecting the work of many, indicates that (1) expression of specific gangliosides, not generally found in high concentrations in most normal human cells, can be linked to certain types of cancer. (2) Gangliosides can affect the ability of cells to interact either directly or indirectly with growth factor receptors, thereby changing such things as a cell’s mobility, rate of proliferation, and metastatic ability. (3) Anti-ganglioside antibodies have been tested, with some success, as potential treatments for certain cancers. (4) Cancer-associated gangliosides shed into the circulation can (a) affect immune cell responsiveness either positively or negatively, (b) be considered as diagnostic markers, and (c) be used to look for recurrence. (5) Cancer registries enable investigators to evaluate data from sufficient numbers of patients to obtain information about potential therapies. Despite advances that have been made, a discussion of possible approaches to identifying additional treatment strategies to inhibit metastasis, responsible for the majority of deaths of cancer patients, as well as for treating therapy-resistant tumors, is included.