ABSTRACT
Amphiphilic calix[4]arenes, functionalized with guanidinium groups, are used to decorate the outer surface of liposomes and significantly improve the cellular uptake of a cargo compared to plain liposomes. The improved uptake is elicited and mediated by the interaction between the cationic polar heads of the macrocycle units embedded in the liposome bilayer and anionic heparan-sulfate proteoglycans surrounding the exterior of cells.
Subject(s)
LiposomesABSTRACT
DC-SIGN is a receptor protruded from the membrane of immature dendritic cells (DCs) that participates in the activation of the immune response through the recognition of pathogen-associated molecular patterns (PAMPs). On the other hand, HIV exploits the interaction between high-mannose structures of its envelope glycoprotein gp120 and DC-SIGN to be transported towards and infect T-cells. DC-SIGN is involved in the recognition process in the form of a tetramer and the multiple exposition of carbohydrate recognition sites (CRSs) is amplified by the formation on the DCs membrane of patches of tetramers. DC-SIGN is then considered an interesting target to fight the virus and multivalent systems exposing multiple copies of ligating units for its CRSs are becoming valuable tools to reach this goal. We herein prepared four mannosylated calix[n]arenes (1a-d) and tested them by Surface Plasmon Resonance (SPR) competition assays as inhibitors of the binding between DC-SIGN and a mannosylated BSA used as model of HIV gp120. IC50s in the µM range were found evidencing in particular for compound 1a that, although rather moderate, a multivalent effect is taking place in the inhibition activity of this cluster. A relative potency (rp/n) around 4, respect to the monovalent methyl α-mannoside and normalized for the number of monosaccharide on the scaffold, was observed. This result, compared with previously reported data relative to dendrimers with the same valency, indicates the calixarene as a promising scaffold to build efficient inhibitors for DC-SIGN and, in perspective, for HIV.
Subject(s)
Cell Adhesion Molecules/chemistry , Lectins, C-Type/chemistry , Peptides/chemistry , Receptors, Cell Surface/chemistry , Dendrimers/chemistry , Dendritic Cells/metabolism , HIV Envelope Protein gp120/chemistry , Humans , Surface Plasmon ResonanceABSTRACT
We recently reported on the activity of cationic amphiphiles in inhibiting TLR4 activation and subsequent production of inflammatory cytokines in cells and in animal models. Starting from the assumption that opportunely designed cationic amphiphiles can behave as CD14/MD-2 ligands and therefore modulate the TLR4 signaling, we present here a panel of amphiphilic guanidinocalixarenes whose structure was computationally optimized to dock into MD-2 and CD14 binding sites. Some of these calixarenes were active in inhibiting, in a dose-dependent way, the LPS-stimulated TLR4 activation and TLR4-dependent cytokine production in human and mouse cells. Moreover, guanidinocalixarenes also inhibited TLR4 signaling when TLR4 was activated by a non-LPS stimulus, the plant lectin PHA. While the activity of guanidinocalixarenes in inhibiting LPS toxic action has previously been related to their capacity to bind LPS, we suggest a direct antagonist effect of calixarenes on TLR4/MD-2 dimerization, pointing at the calixarene moiety as a potential scaffold for the development of new TLR4-directed therapeutics.
Subject(s)
Calixarenes/chemistry , Calixarenes/pharmacology , Lectins/pharmacology , Lipopolysaccharides/pharmacology , Toll-Like Receptor 4/metabolism , Animals , Drug Evaluation, Preclinical/methods , Guanidine/chemistry , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Ligands , Lipopolysaccharide Receptors/metabolism , Lymphocyte Antigen 96/metabolism , Mice, Inbred BALB C , Molecular Docking Simulation , Molecular Dynamics Simulation , Signal Transduction/drug effects , Toll-Like Receptor 4/antagonists & inhibitorsABSTRACT
Correction for 'Moulding calixarenes for biomacromolecule targeting' by Marta Giuliani et al., Chem. Commun., 2015, 51, 14140-14159.
ABSTRACT
After their successful use as a preorganized platform for the preparation of receptors for metal ions and small neutral molecules over the last 15 years, calixarenes are enjoying a renaissance of popularity as scaffolds for ligands that are able to efficiently and selectively target macromolecules such as proteins/enzymes, nucleic acids and lipids. This feature article summarizes the peculiar factors characterizing the calixarene structure and properties, as well as outlines the main rules that can be used to turn such macrocycles into efficient and successful ligands for these classes of biomacromolecules. Factors that affect the multivalent properties of calixarenes, such as the size, conformation and stereochemical presentation of binding groups or their amphiphilicity and hybrid character, are described in detail with the use of a few selected examples from the literature. Perspectives and applications of these ligands in bionanotechnology and nanomedicine, such as protein sensing and inhibition, gene-delivery, targeted drug-delivery and cell imaging, are also discussed.
