Search

Glycan-mediated interactions play a crucial role in biology and medicine, influencing signalling, immune responses, and disease pathogenesis. However, the use of glycans in biosensing and diagnostics is limited by cross-reactivity, as certain glycan motifs can be recognised by multiple biologically distinct protein receptors. To address this specificity challenge, we report the enzymatic synthesis of a 150-member library of site-specifically fluorinated Lewisx analogues ('glycofluoroforms') using naturally occurring enzymes and fluorinated monosaccharides. Subsequent incorporation of a subset of these glycans into nanoparticles or a microarray revealed a striking spectrum of distinct binding intensities across different proteins that recognise Lewisx. Notably, we show that for two proteins with unique binding sites for Lewisx, glycofluoroforms exhibited enhanced binding to one protein, whilst reduced binding to the other, with selectivity governed by fluorination patterns. We finally showcase the potential diagnostic utility of this approach in glycofluoroform-mediated bacterial toxin detection by lateral flow. Distinguishing between different proteins that each bind to the same type of glycan is challenging. Here, the authors demonstrate that an enzymatically synthesised library of Lewisx 'glycofluoroforms' that feature site-specific fluorination can discriminate closely related proteins. [ABSTRACT FROM AUTHOR]

Two novel deep-blue multi-resonance thermally activated delayed fluorescence (MR-TADF) emitters, 1B-CzCrs and 2B-CzCrs, containing a fused carbazole unit were synthesized. The carbazole contributed to the emergence of TADF in these small molecules. Particularly, organic light-emitting diodes with 1B-CzCrs doped in the mCP host achieve a maximum external quantum efficiency of 12.8% at CIE coordinates of (0.146, 0.062). [ABSTRACT FROM AUTHOR]

The PDZ (Postsynaptic density protein-95[PSD-95]/Discs-large) domain, prevalent as a recognition module, has attracted significant attention given its ability to specifically recognize ligands with consensus motifs (also termed PDZ binding motifs [PBMs]). PBMs typically bear a C-terminal carboxylate as a recognition handle and have been extensively characterized, whilst internal ligands are less well known. Here we characterize a short linear motif (SLiM) — EESTSFQGP — as an internal PBM based on its strong binding affinity towards the SHANK1 PDZ domain (SHANK1656–762 hereafter referred to as SHANK1). Using the acetylated analogue Ac-EESTSFQGP-CONH2 as a competitor for the interaction of SHANK1 with FAM-Ahx-EESTSFQGP-CONH2 or a typical fluorophore-labelled C-terminal PBM — GKAP — FITC-Ahx-EAQTRL-COOH — the internal SLiM was demonstrated to show comparable low-micromolar IC50 by competition fluorescent anisotropy. To gain further insight into the internal ligand interaction at the molecular level, we obtained the X-ray co-crystal structure of the Ac-EESTSFQGP-CONH2/SHANK1 complex and compared this to the Ac-EAQTRL-COOH/SHANK1 complex. The crystallographic studies reveal that the SHANK1 backbones for the two interactions overlap significantly. The main structural differences were shown to result from the flexible loops which reorganize to accommodate the two PBMs with distinct lengths and terminal groups. In addition, the two C-terminal residues Gly and Pro in Ac-EESTSFQGP-CONH2 were shown not to participate in interaction with the target protein, implying further truncation and structural modification using peptidomimetic approaches on this sequence may be feasible. Taken together, the SLiM Ac-EESTSFQGP-CONH2 holds potential as an internal ligand for targeting SHANK1. [ABSTRACT FROM AUTHOR]

Quantitative and selective labelling of proteins is widely used in both academic and industrial laboratories, and catalytic labelling of proteins using transpeptidases, such as sortases, has proved to be a popular strategy for such selective modification. A major challenge for this class of enzymes is that the majority of procedures require an excess of the labelling reagent or, alternatively, activated substrates rather than simple commercially sourced peptides. We report the use of a coupled enzyme strategy which enables quantitative N‐ and C‐terminal labelling of proteins using unactivated labelling peptides. The use of an aminopeptidase in conjunction with a transpeptidase allows sequence‐specific degradation of the peptide by‐product, shifting the equilibrium to favor product formation, which greatly enhances the reaction efficiency. Subsequent optimisation of the reaction allows N‐terminal labelling of proteins using essentially equimolar ratios of peptide label to protein and C‐terminal labelling with only a small excess. Minimizing the amount of substrate required for quantitative labelling has the potential to improve industrial processes and facilitate the use of transpeptidation as a method for protein labelling. [ABSTRACT FROM AUTHOR]

Four bis[2‐{pyrazol‐1‐yl}‐6‐{pyrazol‐3‐yl}pyridine] ligands have been synthesized, with butane‐1,4‐diyl (L1), pyrid‐2,6‐diyl (L2), benzene‐1,2‐dimethylenyl (L3) and propane‐1,3‐diyl (L4) linkers between the tridentate metal‐binding domains. L1 and L2 form [Fe2(μ−L)2]X4 (X−=BF4− or ClO4−) helicate complexes when treated with the appropriate iron(II) precursor. Solvate crystals of [Fe2(μ−L1)2][BF4]4 exhibit three different helicate conformations, which differ in the torsions of their butanediyl linker groups. The solvates exhibit gradual thermal spin‐crossover, with examples of stepwise switching and partial spin‐crossover to a low‐temperature mixed‐spin form. Salts of [Fe2(μ−L2)2]4+ are high‐spin, which reflects their highly twisted iron coordination geometry. The composition and dynamics of assembly structures formed by iron(II) with L1−L3 vary with the ligand linker group, by mass spectrometry and 1H NMR spectroscopy. Gas‐phase DFT calculations imply the butanediyl linker conformation in [Fe2(μ−L1)2]4+ influences its spin state properties, but show anomalies attributed to intramolecular electrostatic repulsion between the iron atoms. [ABSTRACT FROM AUTHOR]

A family of macrocyclic bisindolylmaleimides whose diversity stems from the quite distinct regions of conformational space which they populate is described. The compounds are used to compare the diversity and similarity of protein kinases in chemical fashion and this approach allows the conformations of ligands that are best recognized by particular protein kinases to be identified.

Treatment of 2,4,6‐trifluoropyridine with sodium imidazolate, then 2 equiv. sodium pyrazolate, in two reaction steps yields the title ligand L in 40 % overall yield. Crystalline [FeL2][BF4]2 and [FeL2][ClO4]2 are isostructural high‐spin complexes, with highly twisted six‐coordinate geometries and pendant imidazolyl groups. Conversely, [Ag(µ‐L)]BF4·0.5MeCN is a linear coordination polymer of distorted square planar silver ions linked by κ1:κ3,µ‐L ligands. Some samples of [FeL2][BF4]2 were contaminated by [FeIII3(µ‐F)2F6L8]BF4, which was prepared in pure form following reaction of Fe[BF4]2·6H2O, Na3[FeF6] and L in appropriate ratios. The linear [{trans‐FeFL4}2(µ‐F)2FeF4]+ assembly is supported by monodentate L ligands coordinated through their imidazolyl donors, and donating C–H····F interactions to the central [FeF6]3– moiety. The cluster exhibits moderate antiferromagnetic coupling between its iron(III) centres. [ABSTRACT FROM AUTHOR]

Three alkaloids are prepared in stereocontrolled fashion from a common tetraoxobispidine precursor. Reasons for the inherent C2-type regioselectivity of net double nucleophilic additions to tetraoxobispidines are discussed.

The studies have shown that the thermodynamic signature for binding Ar[Gly.sub.n][O.sup.-] ligands to bovine carbonic anhydrase II (BCA II) is derived from an increase in protein dynamics, rather than ligand dynamics, with respect to [Gly.sub.n] chain length. The thermodynamic binding signature is not explained by residual ligand dynamics in the bound state, but has resulted from the indirect influence of ligand chain length on protein dynamics.