Heparin is a vital biomolecule in widespread clinical use as an anti-coagulant. Heparin sensors have potential applications in the bedside detection of heparin levels in human blood during surgery, while high-affinity heparin binders may enable the development of effective heparin reversal agents for use in patients once surgery is complete. However, human blood is a challenging medium in which to achieve selective high-affinity molecular recognition, and as such, this system provides a fascinating challenge to supramolecular chemists. This has encouraged research using a variety of different systems and is stimulating new approaches to the application of molecular recognition. This review article provides an overview of research from both clinical and supramolecular communities towards heparin binding and sensing and considers how this area may develop in the future.

A novel ciprofloxacin–siderophore Trojan Horse antimicrobial was prepared by incorporating key design features of salmochelin, a stealth siderophore that evades mammalian siderocalin capture via its glycosylated catechol units. Assessment of the antimicrobial activity of the conjugate revealed that attachment of the salmochelin mimic resulted in decreased potency, compared to ciprofloxacin, against two Escherichia coli strains, K12 and Nissle 1917, in both iron replete and deplete conditions. This observation could be attributed to a combination of reduced DNA gyrase inhibition, as confirmed by in vitro DNA gyrase assays, and reduced bacterial uptake. Uptake was monitored using radiolabeling with iron-mimetic 67Ga3+, which revealed limited cellular uptake in E. coli K12. In contrast, previously reported staphyloferrin-based conjugates displayed a measurable uptake in analogous 67Ga3+ labeling studies. These results suggest that, in the design of Trojan Horse antimicrobials, the choice of siderophore and the nature and length of the linker remain a significant challenge.

Bacteria use siderophores to mediate the transport of essential Fe(III) into the cell. In Campylobacter jejuni the periplasmic binding protein CeuE, an integral part of the Fe(III) transport system, has adapted to bind tetradentate siderophores using a His and a Tyr side chain to complete the Fe(III) coordination. A series of tetradentate siderophore mimics was synthesized in which the length of the linker between the two iron-binding catecholamide units was increased from four carbon atoms (4-LICAM4−) to five, six and eight (5-, 6-, 8-LICAM4−, respectively). Co-crystal structures with CeuE showed that the inter-planar angles between the iron-binding catecholamide units in the 5-, 6- and 8-LICAM4− structures are very similar (111°, 110° and 110°) and allow for an optimum fit into the binding pocket of CeuE, the inter-planar angle in the structure of 4-LICAM4− is significantly smaller (97°) due to restrictions imposed by the shorter linker. Accordingly, the protein-binding affinity was found to be slightly higher for 5- compared to 4-LICAM4− but decreases for 6- and 8-LICAM4−. The optimum linker length of five matches that present in natural siderophores such as enterobactin and azotochelin. Site-directed mutagenesis was used to investigate the relative importance of the Fe(III)-coordinating residues H227 and Y288.

, https://www.york.ac.uk/chemistry/ Dedicated to Prof. Bernt Krebs on the occasion of his 80 th birthday Highlights  Synthesis of a mimic of the tetradentate stealth siderophore salmochelin S1  The periplasmic binding protein of Vibrio cholerae (VctP) binds the mimic strongly  VctP selects for-configured Fe(III) complexes of the mimic  VctP displays a preference for bis(catecholate) over tris(catecholate) siderophores  The role of salmochelin in iron uptake by pathogens merits further investigation

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