Aqueous self-assembly of molecular building blocks into ordered architectures, polymers and materials opens exciting avenues for fundamental developments in nanoscience and applications in biomedical technologies, optoelectronics and catalysis (Chem. Rev. 2016). Taking inspiration from protein functionality in their biological setting, the Besenius lab has produced electrostatic- and redox-regulated supramolecular polymerisations in water (Angew. Chem. 2013, Chem. Eur. J. 2015). The supramolecular monomer designs we have developed are based on β-sheet encoded anionic and cationic peptides that form anisotropic supramolecular copolymers with a nanorod-like morphology. By doing so the materials becomes stimuli-responsive and polymerizations can be turned on and off in response to pH- and redox-triggers. We have shown that the pH-triggered monomer-polymer transition is simply tuned via thermodynamically controlled comonomer affinities (Polym. Chem. 2015), whereas kinetically controlled assemblies are achieved by coupling multiple equilibria through enzyme catalysed processes (Angew. Chem. 2017), or by confining the self-assembly process onto metallic surfaces (Angew. Chem. 2016, Faraday Discuss. 2017).

In order to establish a set of semi-empirical rules for the design of supramolecular nanomaterials we often use the concept of frustrated self-assembly, which describes the balance of positive non-covalent interactions with repulsive forces. Here, we either use electrostatic interactions to tune the repulsive contribution in the frustrated self-assembly (J. Mater. Chem. B 2013, Org. Biomol. Chem. 2015), or we rely on steric constraints in order to induce frustration and restrict the one-dimensional self-assembly into well-defined nanorods in water (Chem. Eur. J. 2015). In view of recent reports that anisotropic shapes in the design of biomedical carrier materials outperform conventional isotropic structures, we are particularly interested in the development of supramolecular multifunctional materials and their biomedical applications. For example, we aim to explore applications in immunotherapy (ChemBioChem 2018, 912 & 1142), where we attach a variety of glycopeptide epitopes onto the self-assembling constructs that can activate the immune system for a selective response towards molecular defined specific antigens. Multipotent fully synthetic vaccines, can thus be developed conveniently using a supramolecular engineering approach that rely on the simple mixing of multifunctional monomeric building blocks.

Spatial and temporal control in multistimuli-responsive structures are key properties to advance and optimize functional soft matter. In an attempt to develop autonomous non-equilibrium states in supramolecular polymers, and hydrogel materials, we have expanded the above concept of ß–sheet self-assembly of alternating hydrophilic and hydrophobic amino acids. An interplay of pH- and oxidation-stimuli, promoted by the production of reactive oxygen species (ROS) thus lead to transient supramolecular polymerisations, with tuneable lifetimes and stabilities (Angew. Chem. 2017). In addition, the monomers can be equipped with thermoresponsive triethylene glycol chains, which in the polymeric state lead to a thermogelation process at a biomedically relevant temperature of 30-35 °C. Since reactive oxygen species play an important role in signal transduction cascades, our materials offer great potential for applications of these dynamic biomaterials in redox microenvironments.

We further aim to study the fundamentals of the supramolecular polymerisation mechanism, the thermodynamics which dictate the size and stability of the colloidally stable polymers, as well as kinetic parameters and non-equilibrium states (Macromolecules 2017). Most recently we were able to extend the design rules from small molecular weight building blocks to macromolecular designs that upon folding produce viromimetic particles, with a densely ordered peptide core, that is surrounded by a shielding and protein repelling core of hydrophilic polymer (Chem. Commun. 2018). A reduction of the pH leads to disassembly, and the pH stability window for the particles follow the same behaviour as protein-based assemblies, like virus particles.

A recent research strategy in the Besenius group involves the design of a new class of hybrid bioorganic Au(I)-peptide materials. The aim is to couple molecular Au(I)-complexes to small peptide building blocks, in order to prepare new metalloamphiphiles as supramolecular monomers. Structurally and functionally the aurophilic interaction between Au(I)-centres is at the heart of these systems. We have developed a facile synthetic route for the preparation of stable peptidic Au(I)-metalloamphiphiles equipped with stabilising phosphane ligands (Chem. Commun. 2015). Using a diphenylalanine derivative, we have shown that the Au(I)-metalloamphiphile self-assembles into luminescent micellar nanostructures in buffered aqueous environments of medium to high ionic strength. We have extended the ligation strategy for Diels-Alder conjugation and biotinylation of Au(I)-complexes (Chem. Eur. J. 2017). The attractive feature of the Au(I)-complexes, are their phosphorescent properties which depend on the tuneable distance between the gold centres, as wells as the long lifetimes of the excited states. This new class of bioinorganic hybrid materials hold great promise for chemo- and biosensors, and for the preparation of ultrathin and mechanosensitive luminescent nanowires. A spectacular finding which holds great promise for further efforts in the above-mentioned applications, is a recently discovered stepwise self-assembly of a Au^I-metallopeptides in water. Here we achieved kinetic control of the supramolecular polymer morphology using a temperature-dependent assembly protocol, which yields low dispersity supramolecular polymers, a metastable state at low temperature or helical bundled nanorods, at higher temperatures (J. Am. Chem. Soc. 2018).

The main and most important feature of vaccines is the induction of an immunological memory response, which is key to providing long-term protection against pathogens. The current strategies for potent antibacterial and antiviral vaccines employ conjugation of pathogen specific entities onto carrier proteins, and are limited to formulations that suffer from low stability and short shelf-lives, and are thus not viable in developing countries. Strategies for the development of new vaccinations against endogenous diseases like cancer further remain an unmet challenge, since current methodologies suffer from a lack of a modular and tailored vaccine-specific functionalisation. SupraVacc therefore proposes a new design approach for the development of fully synthetic molecular vaccines, using carbohydrate and glycopeptide appended epitopes that are grafted onto supramolecular building blocks. These units can be individually designed to attach disease specific antigens and immunostimulants. Due to their self-assembling properties into nanoscaled pathogen mimetic particles, they serve as a supramolecular subunit vaccine toolbox. By developing a universal supramolecular polymer platform, we will construct multipotent vaccines from glycan-decorated peptides, that combine the activity of protein conjugates with the facile handling, precise composition and increased stability of traditional small molecule pharmaceutical compounds. SUPRAVACC will pioneer the design of minimalistic and broadly applicable vaccines, and will evaluate the supramolecular engineering approach for immunisations against antibacterial diseases, as well as for applications as antitumour vaccine candidates.

The Besenius lab gratefully acknowledges financial support from the following organisations:

Our laboratory is well equipped with facilities for the synthesis and characterisation of organic, peptide and supramolecular materials.
Further information about the core facilities of the Department of Chemistry can be found below.

Analytical Core Facility at the Department of Chemistry