Making molecules work - stories of supramolecular translation

Abstract

Commercialising supramolecular chemistry has proved challenging, but encouraging stories are beginning to emerge. In this editorial we present accounts of programs aimed at diabetes management, humidity sensing, antimicrobials, shock absorbing materials, nitrate sensing and anti-cancer agents. The experiences of the authors are intended to help others following similar paths, assisting efforts to develop real-world applications of functional molecules.

Fig. 1. (a) The monocyclic glucose receptor 1 which led to the foundation of Ziylo. (b) GluHUT 2, the glucose receptor that really works, with a model of its complex with β-glucose.

Fig. 2. A concept for glucose-sensitive insulin (GSI). A glucose receptor and a glucosyl unit are attached at different points to the insulin peptide. In the absence of glucose they come together, rendering the insulin inactive due to a change in conformation (or some other reason). In the presence of glucose, the glucosyl unit is displaced and the insulin becomes active.

Fig. 3. The OPTOSENSE journey. It started from failed experiments which, after thorough studies on the photochemistry of hydroxyazobenzenes in polymer thin films, turned into commercialization efforts and two generations of proof-of-concept devices. The journey continues and has also sparked other commercialization efforts in our group related to dynamic cell culture platforms and reconfigurable optical elements for augmented/mixed reality technologies.

Fig. 4. An example SSA, TBA = tetrabutylammonium. This SSA is intrinsically fluorescent due the presence of a benzothiazole functionality. In polar organic solvents, such as DMSO, we have evidence to support the formation of anionic, hydrogen bonded dimers, such as those identified in the solid state through single crystal X-ray diffraction studies. In water, this same SSA is shown to self-associate, this time producing spherical aggregates such as those identified through solution state fluorescence microscopy. However, upon the addition of salts, such as NaCl, followed by an annealing process, these spherical aggregates morph into fibres (also characterised through solution state fluorescence microscopy), resulting in the formation of hydrogels, with minimum gelation concentrations as low as 1.5 mg mL⁻¹.

Fig. 5. (a) A cartoon depicting the structure of the talin, including the R1–R13 domains which give this protein its shock absorbing properties. The R1–R3 domains used to produce the TSAM protein monomer have been highlighted in orange. (b) The structure of, and reaction between, the TSAM protein monomer and the synthetic tripodal linker used to produce the TSAM itself. (c) Cartoon illustrating the hypothesised response of the TSAM monomeric units, contained within the TSAM hydrogel, upon the application of force. (d) Experimental setup used to test the capability of the TSAM to absorb the impact of projectiles (basaltic particles) shot at 1.5 km s⁻¹ into a 5 mm depth of TSAM (200 mg per mL protein monomer). (e) Images of TSAM material post shot. Here the material is intact and the spherical basaltic particles that have impacted the TSAM can be seen incapsulated within the material. Images of a control experiment in which a commercially available polyvinylpyrrolidone hydrogel has been destroyed under analogous shot conditions, and damage to a metal back plate incurred due to the failure of the control material.

Fig. 6. (Top) Vials containing two different arylethynyl bisurea anion receptors screened for their fluorescent response to anions; (bottom) hydrogen bonding receptors showing fluorescent response to various anions.

Fig. 7. Polymer film containing a small amount of the nitrate-sensing receptor molecule under normal (left) and UV (right) light.

Fig. 8. Structure of the free-base form of texaphyrin. It acts as a monoanionic ligand and is stabilized through metal cation complexation. In the bulk of the studies referred to in this section, the metal cation is Gd(iii).

Fig. 9. FDA-approved platinum agents cisplatin, carboplatin, and oxaliplatin. Also shown are the structures of two texaphyrin drug conjugates, namely 4 and OxaliTEX (5).

Fig. 10. Efficacy study of A549 human lung cancer hind flank tumour xenografts in mice. The comparison involves the intravenous administration of four doses each of 4 and OxaliTEX (5) over two weeks. TDC 4 was administered at the maximum tolerated dose (MTD) and 5 was administered at a dose that was ∼85% of the MTD. Error bars represent the standard error.

Fig. 11. Treatment of a patient-derived xenograft (PDX) tumour of a platinum-resistant wt-p53 serous ovarian cancer in mice with clinicians’ choice carboplatin compared to OxaliTEX (5).