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.

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.

No abstract

Two pyrene based organogelators in which the pyrene moiety has been linked to the diphenylalanine dipeptide have been synthesized. We show how the solvent can tune both the morphology and the optical properties of the organogels: spherical aggregates with quenched emission were obtained in acetonitrile, whereas an entangled fibrillar network with enhanced emission was formed in o-dichlorobenzene. Fourier transform infrared spectroscopy, circular dichroism and nuclear magnetic resonance spectroscopy experiments suggest that both π-π stacking and hydrogen bonding contribute to the formation of the supramolecular networks. Ultraviolet-visible and steady state emission studies demonstrated the formation of I-aggregates in acetonitrile. In contrast, in o-dichlorobenzene, the formation of J-type aggregates leads to assemblies with enhanced emission. These results give some insight into the important role of the gelling solvent in the morphology of the supramolecular gels and may help in the design of new soft-materials.

Liposomes equipped at the outer membrane with positively charged calixarenes show improved efficiency in cargo delivery. This is facilitated by the interaction between the macrocycle units and heparan sulfate proteoglycans surrounding the cell.