Stuart L. Warriner

Covalent protein modification can facilitate the elucidation of biological mechanisms and serve as a powerful strategy for drug discovery. The discovery of protein modifiers may be initiated by screens of diverse sets of reactive fragments. A modular synthesis of diverse pentafluorobenzenesulfonamide reactive fragments was developed, which was based on the reaction between diverse, readily‐available substrates and rhodium nitrenoid intermediates formed from pentafluorobenzenesulfonamide. The approach enabled the synthesis of 21 reactive fragments whose diversity stemmed from both that of the substrates and the rich chemistry of rhodium nitrenoids. The fragments were found to modify Aurora A kinase via several distinct pathways. Furthermore, five of the reactive fragments were profiled against HeLa cell lysate, which demonstrated that the constellation of modified cysteines was critically dependent on the specific reactive fragment used. Overall, the modular Rh‐catalyzed connective approach enabled the synthesis of reactive fragments with high structural and reactivity diversity. We envisage that such reactive fragments may provide useful starting points for the discovery of covalent modifiers of proteins, including chemical probes and drugs.

Covalent modification, by substitution of pentafluorobenzene sulfonamides, can enable understanding and modulation of protein function, and the identification of new therapeutic opportunities.

Isocyanides have been explored as bioorthogonal triggers for uncaging reactions. However, our findings show they can covalently label proteins, indicating they may not be fully bioorthogonal in biological systems.

We report the use of an extended -conjugated electron-deficient “pyrazino[2,3-g]quinoxaline (PQ)” as a strong, planar acceptor in a donor-acceptor thermally activated delayed fluorescence emitter design to achieve deep-red to NIR emission. A pair of multi-donor-acceptor (multi-D-A) emitters, 4DMAC-TPPQ and 4PXZ-TPPQ, using PQ as the strong acceptor and dimethylacridine (DMAC) and phenoxazine (PXZ) as strong donors, respectively, emit at 650 and 762 nm in toluene, which is significantly red-shifted in comparison to the parent compound TPPQ (PL = 456 nm). Both compounds show aggregation-induced emission enhancement in THF:water mixtures. Both compounds are TADF as doped films in 4,4′-bis(N-carbazolyl)-1,1′-biphenyl (CBP) and as neat films. The emission of the neat film is similar to that in toluene with PL of 654 and 770 nm for 4DMAC-TPPQ and 4PXZ-TPPQ, respectively. Solution-processed organic light-emitting diodes (SP-OLEDs) of neat 4DMAC-TPPQ showed electroluminescence (EL) at 685 nm and EQEmax of 0.3%, while the device with 4PXZ-TPPQ emitted at EL of 780 nm and showed an EQEmax of 0.04%. The OLEDs with 4PXZ-TPPQ showed the most red-shifted emission amongst those employing TADF emitters containing a quinoxaline-type acceptor.

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^x 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 Lewis^x. Notably, we show that for two proteins with unique binding sites for Lewis^x, 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.

Two novel deep-blue multi-resonant thermally activate delayed fluorescnece (MR-TADF) emitters, 1B-CzCrs and 2B-CzCrs, containing a 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 mCP host achieve a maximum external quantum efficiency of 12.8% at CIE coordinates of (0.146, 0.062).

Thermally activated delayed fluorescence (TADF) compounds are highly attractive as sensitising and emitting materials for organic light-emitting diodes (OLEDs) as they can harvest both singlet and triplet excitons and convert them into light. In this study we designed a series of derivatives of the widely studied donor-acceptor TADF emitter DMAC-TRZ with the objective of correlating their structure to their propensity to orient horizontally in vacuum-deposited doped thin films. This is important as the preferential horizontal orientation of the transition dipole moment (TDM) of the emitter, which tends to co-align with the long axis of D-A compounds, leads to enhanced light-outcoupling, and therefore higher maximum external quantum efficiencies (EQEmax) of the OLED. The decoration of the DMAC donor with substituted aryl groups also affects the emission color and the capacity for the emitters to efficiently harvest triplet excitons. The presence of electron-withdrawing 4-cyanophenyl and 4-trifluoromethylphenyl groups in, respectively, CNPh-DMAC-TRZ and CF3Ph-DMAC-TRZ blue-shifts the emission spectrum but slows down the reverse intersystem crossing rate constant (kRISC), while the opposite occurs in the presence of electron-donating groups in tBuPh-DMAC-TRZ and OMePh-DMAC-TRZ (red-shifted emission spectrum and faster kRISC). In contrast to our expectations, the OLED performance of the five DMAC-TRZ derivatives does not scale with their degree of horizontal emitter orientation but follows the kRISC rates. This, in turn, demonstrates that triplet harvesting (and not horizontal emitter orientation) is the dominant effect for device efficiency. Nonetheless, highly efficient OLEDs were fabricated with tBuPh-DMAC-TRZ and OMePh-DMAC-TRZ as emitters, with improved EQEmax (~ 28%) compared to the reference DMAC-TRZ devices.

Narrowband emissive multiresonant thermally activated delayed fluorescence (MR-TADF) emit-ters are a promising solution to achieve the current industry targeted color standard, BT.2020, for blue color without using optical filters, aiming for high efficiency organic light-emitting di-odes (OLEDs). However, their long triplet lifetimes, largely affected by their slow reverse inter-system crossing rates, adversely affect device stability. In this study, a helical MR-TADF emitter (f-DOABNA) has been designed and synthesized. Because of its -delocalized structure, f-DOABNA possesses a small singlet-triplet gap, EST, and displays simultaneously an exception-ally faster reverse intersystem crossing rate constant, kRISC, of up to 2 × 106 s1 and a very high photoluminescence quantum yield, PL, of over 90% in both solution and doped films. The OLED with f-DOABNA as the emitter achieved a narrow deep-blue emission at 445 nm (full width at half-maximum of 24 nm) associated with CIE coordinates of 0.150, 0.041, and showed a high maximum external quantum efficiency, EQEmax, of ~20%.

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.

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.