Lipid bilayer membranes form compartments requisite for life. Interfacing supramolecular systems, including receptors, catalysts, signal transducers and ion transporters, enables the function of the membrane to be controlled in artificial and living cellular compartments. In this perspective, we take stock of the current state of the art of this rapidly expanding field, and discuss prospects for the future in both fundamental science and applications in biology and medicine.

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Supramolecular chemistry in lipid bilayer membranes.

Orientational self-sorting: formation of structurally defined Pd4L8 and Pd6L12 cages from low-symmetry dipyridyl ligands.

Abstract Mechanically interlocked molecules present opportunities to construct therapeutic drugs and diagnostic imaging agents but harnessing supramolecular chemistry to make biologically active probes in water is a challenge. Here, we describe a rotaxane‐based approach to synthesise radiolabelled proteins and peptides for molecular imaging of cancer biomarkers in vivo. Host–guest chemistry using β‐cyclodextrin‐ and cucurbit[6]uril‐catalysed cooperative capture synthesis produced gallium‐68 or zirconium‐89 radiolabelled metallo[4]rotaxanes. Photochemical conjugation to trastuzumab led to a viable positron emission tomography (PET) radiotracer. The rotaxane architecture can be tuned to accommodate different radiometal ion complexes, other protein‐ or peptide‐based drugs, and fluorophores for optical detection. This technology provides a platform to explore how mechanical bonding can improve drug delivery, enhance tumour specificity, control radiotracer pharmacokinetics, and reduce dosimetry.

Supramolecular Rotaxane‐Based Multi‐Modal Probes for Cancer Biomarker Imaging

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/1873-3468.14535

Bioinorganic supramolecular coordination complexes and their biomedical applications

Cuboctahedral coordination cages of the general formula [Pd12L24]24+ (L = low-symmetry ligand) were analyzed theoretically and experimentally. With 350 696 potential isomers, the structural space of these assemblies is vast. Orientational self-sorting refers to the preferential formation of particular isomers within the pool of potential structures. Geometric and computational analyses predict the preferred formation of cages with a cis arrangement at the metal centers. This prediction was corroborated experimentally by synthesizing a [Pd12L24]24+ cage with a bridging 3-(4-(pyridin-4-yl)phenyl)pyridine ligand. A crystallographic analysis of this assembly showed exclusive cis coordination of the 3- and the 4-pyridyl donor groups at the Pd2+ ions.

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Orientational self-sorting in cuboctahedral Pd cages

Bioconjugate Supramolecular Pd2+ Metallacages Penetrate the Blood Brain Barrier In Vitro and In Vivo.

In living cells, communication requires the action of membrane receptors that are activated following very small environmental changes. A binary all-or-nothing behavior follows, making the organism extremely efficient at responding to specific stimuli. Using a minimal system composed of lipid vesicles, chemical models of a membrane receptor and their ligands, we show that bio-mimetic ON/OFF assembly of high avidity, multivalent domains is triggered by small temperature changes. Moreover, the intensity of the ON signal at the onset of the switch is modulated by the presence of small, weakly binding divalent ligands, reminiscent of the action of primary messengers in biological systems. Based on the analysis of spectroscopic data, we develop a mathematical model that rigorously describes the temperature-dependent switching of the membrane receptor assembly and ligand binding. From this we derive an equation that predicts the intensity of the modulation of the ON signal by the ligand-messenger as a function of the pairwise binding parameters, the number of binding sites that it features and the concentration. The behavior of our system, and the model derived, highlight the usefulness of weakly binding ligands in the regulation of membrane receptors and the pitfalls inherent to their binding promiscuity, such as non-specific binding to the membrane. Our model, and the equations derived from it, offer a valuable tool for the study of membrane receptors in both biological and biomimetic settings. The latter can be exploited to program membrane receptor avidity on sensing vesicles, create hierarchical protocell tissues or develop highly specific drug delivery vehicles.

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Ben Woods

Papers

Bioconjugate Supramolecular Pd2+ Metallacages Penetrate the Blood Brain Barrier In Vitro and In Vivo.

How the biomimetic assembly of membrane receptors into multivalent domains is regulated by a small ligand