Synthesis and screening of a library of Lewis deoxyfluoro-analogues reveals differential recognition by glycan-binding partners.

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 Lewis analogues ('glycofluoroforms') using naturally occurring enzymes and fluorinated monosaccharides.

Molecular asymmetry and rigidification as strategies to activate and enhance thermally activated delayed fluorescence in deep-blue MR-TADF emitters.

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.

Biophysical and structural analyses of the interaction between the SHANK1 PDZ domain and an internal SLiM.

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).

Activation of fluoride anion as nucleophile in water with data-guided surfactant selection.

A principal component was developed for 91 commonly accessible surfactants for use in surfactant-enabled organic reactions in water, an important approach for sustainable chemical processes. This map was built using 22 experimental and theoretical descriptors relevant to the physicochemical nature of these surfactant-enabled reactions, and advanced principal component analysis algorithms. It is comprised of all classes of surfactants, cationic, anionic, zwitterionic and neutral surfactants, including designer surfactants.

Quantitative N- or C-Terminal Labelling of Proteins with Unactivated Peptides by Use of Sortases and a d-Aminopeptidase.

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.

A fluorescent photoaffinity probe for formyl peptide receptor 1 labelling in living cells.

Fluorescent ligands for G-protein coupled receptors (GPCRs) are valuable tools for studying the expression, pharmacology and modulation of these therapeutically important proteins in living cells. Here we report a fluorescent photoaffinity probe for Formyl peptide receptor 1 (FPR1), a critical component of the innate immune response to bacterial infection and a promising target in inflammatory diseases. We demonstrate that the probe binds and covalently crosslinks to FPR1 with good specificity at nanomolar concentrations in living cells and is a useful tool for visualisation and characterisation of this receptor.

Di-Iron(II) [2+2] Helicates of Bis-(Dipyrazolylpyridine) Ligands: The Influence of the Ligand Linker Group on Spin State Properties.

Four bis[2-{pyrazol-1-yl}-6-{pyrazol-3-yl}pyridine] ligands have been synthesized, with butane-1,4-diyl (L ), pyrid-2,6-diyl (L ), benzene-1,2-dimethylenyl (L ) and propane-1,3-diyl (L ) linkers between the tridentate metal-binding domains. L and L form [Fe (μ-L) ]X (X =BF or ClO ) helicate complexes when treated with the appropriate iron(II) precursor. Solvate crystals of [Fe (μ-L ) ][BF ] exhibit three different helicate conformations, which differ in the torsions of their butanediyl linker groups.

Towards identification of protein-protein interaction stabilizers inhibitory peptide-fragment hybrids using templated fragment ligation.

Using the DMX/14-3-3 interaction, acylhydrazone-based ligand-directed fragment ligation was used to identify protein-protein interaction (PPI) inhibitory peptide-fragment hybrids. Separation of the peptide-fragment hybrids into the components yielded fragments that stabilized the DMX/14-3-3 interaction.

Understanding the interaction of 14-3-3 proteins with hDMX and hDM2: a structural and biophysical study.

p53 plays a critical role in regulating diverse biological processes: DNA repair, cell cycle arrest, apoptosis and senescence. The p53 pathway has therefore served as the focus of multiple drug-discovery efforts. p53 is negatively regulated by hDMX and hDM2; prior studies have identified 14-3-3 proteins as hDMX and hDM2 client proteins.

Pyrene Tags for the Detection of Carbohydrates by Label-Assisted Laser Desorption/Ionisation Mass Spectrometry*.

Matrix-assisted laser desorption/ionisation mass spectrometry (MALDI-MS) is widely used for the analysis of biomolecules. Label-assisted laser desorption/ionisation mass spectrometry (LALDI-MS) is a matrix-free variant of MALDI-MS, in which only analytes covalently attached to a laser desorption/ionisation (LDI) enhancer are detected. LALDI-MS has shown promise in overcoming the limitations of MALDI-MS in terms of sample preparation and MS analysis.

Activity-directed expansion of a series of antibacterial agents.

The feasibility of using activity-directed synthesis to drive antibacterial discovery was investigated. An array of 220 Pd-catalysed microscale reactions was executed, and the crude product mixtures were evaluated for activity against Staphylococcus aureus. Scale-up of the hit reactions, purification and evaluation, enabled expansion of a class of antibacterial quinazolinones.

Supramolecular Iron Metallocubanes Exhibiting Site-Selective Thermal and Light-Induced Spin-Crossover.

Treatment of Fe[BF]·6HO with 4,6-di(pyrazol-1-yl)-1-pyrimid-2-one (HL) or 4,6-di(4-methylpyrazol-1-yl)-1-pyrimid-2-one (HL) affords solvated crystals of [{Fe(OH)}⊂Fe(μ-L)][BF] (, HL = HL; , HL = HL). The centrosymmetric complexes contain a cubic arrangement of iron(II) centers, with bis-bidentate [L] ligands bridging the edges of the cube. The encapsulated [Fe(OH)] moiety templates the assembly through 12 O-H···O hydrogen bonds to the [L] hydroxylate groups.

Heterometallic Coordination Polymer Gels Supported by 2,4,6-Tris(pyrazol-1-yl)-1,3,5-triazine.

Complexes of type [M(tpt)]X (M = Fe, Co, Ni; tpt = 2,4,6-tri{pyrazol-1-yl}-1,3,5-triazine; X = BF or ClO ) crystallize in a cubic lattice, with the metal ion and ligand conformation showing unusual symmetry-imposed disorder. Addition of 1 equiv AgX to the corresponding preformed [M(tpt)]X salt in concentrated MeNO solution affords thixotropic gels. Gelation was not observed in analogous reactions using [Mn(tpt)][ClO], or from reactions in other, more donating solvents.

Potent, selective, and subunit-dependent activation of TRPC5 channels by a xanthine derivative.

Background And Purpose: The TRPC1, TRPC4, and TRPC5 proteins form homotetrameric or heterotetrameric, calcium-permeable cation channels that are involved in various disease states. Recent research has yielded specific and potent xanthine-based TRPC1/4/5 inhibitors. Here, we investigated the possibility of xanthine-based activators of these channels.

A catalytic protein-proteomimetic complex: using aromatic oligoamide foldamers as activators of RNase S.

Foldamers are abiotic molecules that mimic the ability of bio-macromolecules to adopt well-defined and organised secondary, tertiary or quaternary structure. Such templates have enabled the generation of defined architectures which present structurally defined surfaces that can achieve molecular recognition of diverse and complex targets. Far less explored is whether this mimicry of nature can extend to more advanced functions of biological macromolecules such as the generation and activation of catalytic function.

A luminescent [PdRu] supramolecular cage.

A phosphorescent cage of the form [Pd4Ru8]24+ is reported. The cage was formed using the metalloligand [Ru(dtbubpy)2(qpy)]2+, where qpy = 4,4':2',2'':4'',4'''-quaterpyridine and dtbubpy = 4,4'-di-tert-butyl-2,2'-bipyridine. The cage has been characterised by NMR, ESI-MS, TEM and X-ray diffraction analyses and its emission properties elucidated by steady-state and time-resolved emission spectroscopy.

Silver(i) complexes of bis- and tris-(pyrazolyl)azine derivatives - dimers, coordination polymers and a pentametallic assembly.

Silver(i) complexes of 2,4,6-tri(pyrazol-1-yl)pyridine (tpp), 2,4,6-tri(pyrazol-1-yl)pyrimidine (tpym), 2,4,6-tri(pyrazol-1-yl)-1,3,5-triazine (tpt) and 2,4-di(pyrazol-1-yl)-1,3,5-triazine (bpt) are reported. Dinuclear [Ag2(μ-tpp)2(MeCN)2][BF4]2·2MeCN and [Ag2(μ-tpym)2(MeCN)2][BF4]2 are formed from approximately planar [AgL(NCMe)]+ (L = tpp or bpym) centres, which dimerise via apical interactions to the pendant pyrazolyl donor on each ligand. Two polymeric solvatomorph phases [Ag2(μ-tpp)2][BF4]2·nMeNO2 were obtained by crystallising AgBF4 and tpp from nitromethane solution.

Double quick, double click reversible peptide "stapling".

The development of constrained peptides for inhibition of protein-protein interactions is an emerging strategy in chemical biology and drug discovery. This manuscript introduces a versatile, rapid and reversible approach to constrain peptides in a bioactive helical conformation using BID and RNase S peptides as models. Dibromomaleimide is used to constrain BID and RNase S peptide sequence variants bearing cysteine (Cys) or homocysteine (Cys) amino acids spaced at and + 4 positions by double substitution.

Towards designer organelles by subverting the peroxisomal import pathway.

The development of 'designer' organelles could be a key strategy to enable foreign pathways to be efficiently controlled within eukaryotic biotechnology. A fundamental component of any such system will be the implementation of a bespoke protein import pathway that can selectively deliver constituent proteins to the new compartment in the presence of existing endogenous trafficking systems. Here we show that the protein-protein interactions that control the peroxisomal protein import pathway can be manipulated to create a pair of interacting partners that still support protein import in moss cells, but are orthogonal to the naturally occurring pathways.

Homochiral Emissive Λ - and Δ -[Ir Pd ] Supramolecular Cages.

Synthetic self-assembly is a powerful technique for the bottom-up construction of discrete and well-defined polyhedral nanostructures resembling the spherical shape of large biological systems. In recent years, numerous Archimedean-shaped coordination cages have been reported based on the assembly of bent monodentate organic ligands containing two or more distal pyridyl rings and square-planar Pd ions. The formation of photoactive Pd metallamacrocycles and cages, however, remain rare.

Economical and scalable synthesis of 6-amino-2-cyanobenzothiazole.

2-Cyanobenzothiazoles (CBTs) are useful building blocks for: 1) luciferin derivatives for bioluminescent imaging; and 2) handles for bioorthogonal ligations. A particularly versatile CBT is 6-amino-2-cyanobenzothiazole (ACBT), which has an amine handle for straight-forward derivatisation. Here we present an economical and scalable synthesis of ACBT based on a cyanation catalysed by 1,4-diazabicyclo[2.

M12L8 metallo-supramolecular cube with cyclotriguaiacylene-type ligand: spontaneous resolution of cube and its constituent host ligand.

The racemic ligand (±)-tris-(4-methylthiazolyl)cyclotriguaiacylene forms a homochiral crystalline Ag12L8 cube with spontaneous resolution. The ligand itself likewise crystallises in a chirally pure fashion in two clathrate complexes. Ag12L8 is the first example of a cyclotriguaiacylene-type coordination cube and a rare example of a M12L8-type metallo-cube.

Peroxisome protein import: a complex journey.

The import of proteins into peroxisomes possesses many unusual features such as the ability to import folded proteins, and a surprising diversity of targeting signals with differing affinities that can be recognized by the same receptor. As understanding of the structure and function of many components of the protein import machinery has grown, an increasingly complex network of factors affecting each step of the import pathway has emerged. Structural studies have revealed the presence of additional interactions between cargo proteins and the PEX5 receptor that affect import potential, with a subtle network of cargo-induced conformational changes in PEX5 being involved in the import process.

Hydrocarbon constrained peptides - understanding preorganisation and binding affinity.

The development of constrained peptides represents an emerging strategy to generate peptide based probes and hits for drug-discovery that address challenging protein-protein interactions (PPIs). In this manuscript we report on the use of a novel α-alkenylglycine derived amino acid to synthesise hydrocarbon constrained BH3-family sequences (BIM and BID). Our biophysical and structural analyses illustrate that whilst the introduction of the constraint increases the population of the bioactive α-helical conformation of the peptide in solution, it does not enhance the inhibitory potency against pro-apoptotic Bcl-x and Mcl-1 PPIs.