Here we report a glycopeptide analogue of somatostatin, selectively activated by β-galactosidase. A solid-phase peptide synthesis compatible glycoamino acid masked the peptide pharmacophore, blocking receptor binding. β-Galactosidase activation in cancer cells enhanced cytotoxicity, demonstrating a model system for targeted peptide delivery and recognition with enzyme-mediated spatiotemporal control.

Peptide macrocyclization offers a versatile method for enhancing peptide stability, cell permeability, and biological activity. Herein, we report a radical-mediated, thiol-yne process for peptide macrocyclization, furnishing vinyl sulfide products. Our robust methodology enables the formation of cyclic peptides under mild conditions, generating a disulfide bioisostere to a range of biologically relevant neuropeptides, identifying a novel vinyl sulfide analogue of oxytocin with enhanced potency and redox stability over the parent compound. Cyclization was achieved using UV-A or blue LED irradiation, in either organic or aqueous solvents. The adaptation of the methodology for late-stage modification of cyclic peptides using maleimide tags is also described, underscoring the broad utility of the method.

This work presents a late-stage aqueous peptide lipidation strategy via the thiol-Michael addition of thiolated lipids at dehydroalanine (Dha). This strategy was used to synthesise lipopeptides containing diacylglycerol (DAG), saturated, unsaturated and cholesterol lipid motifs. The DAG lipopeptide product was found to be a substrate for the lipoprotein processing enzyme, LspA.

Activity-Based Probes (ABPs) are invaluable tools for investigating enzymatic activity but can suffer from onerous syntheses and low stability in complex proteomes. Herein, we present the first synthesis of a robust, vinyl methyl ester (VME), bearing amino acid, which is compatible with solid phase peptide synthesis (SPPS). Novel peptidic probes incorporating the VME motif were prepared, and their labeling activity was investigated against the deubiquitinating enzyme (DUB) Otubain 1 (OTUB1), a critical cysteine protease DUB with remarkable specificity for Lys48 linked polyubiquitin chains. OTUB1 is implicated in DNA repair and immune response mechanisms and is currently considered a biomarker for tumorigenesis. A probe featuring the VME warhead demonstrated high reactivity and selectivity toward OTUB1, highlighting the significant potential of this approach to create robust and selective covalent tools for interrogating cysteine isopeptidases.

The unique nucleophilic and redox properties of the sulfhydryl group render it highly useful as a synthetic handle for the diversification of peptide structure, including macrocyclization, ligation, and bioconjugation. Herein, a sequential acyl-thiol-ene/S-deacetylation protocol for selectively installing thiol residues onto bioactive peptides on-resin is demonstrated. Through judicious placement of appropriate unsaturated residues, the hydrothiolation/S-deacetylation protocol offers a novel synthetic strategy to investigate the structure-activity relationship of disulfide-containing peptides displaying different ring sizes. Furthermore, a new and generally applicable fluorescent labeling strategy is introduced to facilitate direct on-resin conjugation without intermediate purification steps. These new methods provide a robust and versatile platform for peptide macrocyclization and bioconjugation, with broad applications in peptide synthesis and chemical biology.

Effective metallization of super-engineering plastics such as liquid crystal polymers (LCP) and polyphenylene sulfides (PPS) via electroless deposition of copper thin films is an important step in the manufacturing of a wide range of devices. Copper deposition typically requires a pre-treatment step involving chemical and/or mechanical roughening to ensure high adhesion at the polymer/Cu interface; however such treatments are detrimental to patterns and topographic features of the polymer that possess mu m resolution and/or high aspect ratio. Herein, we demonstrate that it is possible to regulate and improve adhesion of electrolessly deposited copper thin films at LCP and PPS materials via multilayer functionalization with aryldiazonium cations of a p-aminobenzoic acid precursor. We first demonstrate that aryldiazonium grafting conditions can be optimized to overcome the chemical inertness of LCP/PPS without resorting to harsh oxidative or mechanical treatments. We then show that the density of Ar-COOH groups can be regulated by modifying the number of functionalization cycles. X-ray photoelectron spectroscopy studies shows that this has a clear impact on the composition of the catalytic nanoparticle layer required for copper deposition. Adhesion strength studies demonstrate that such changes translate into improved adhesion strengths without any adverse effects on surface roughness. Control experiments with alternative chemical moieties suggest that specific chemical interactions between catalytic seeds and grafted carboxylate groups play an important role in the observed improved adhesion.

Four new aromatic imides bearing triphenylamino (TPA) moieties are reported each of which differ by the number and/or positional arrangements of the TPA units. Compounds 1-3 are 1,8-naphthalimides (naps) that contain N,N '-diphenyl-[1,1 '-biphenyl]-4-amino (TPA-Ph) groups appended to the N-termini of the respective imides. Each differs by their functionalisation of the 4-position of the nap: nitro (1), amino (2), or an additional TPA group (3). By contrast, compound 4 is a naphthalene diimide (NDI) functionalised with TPA-Ph moieties on each N-terminus. These simple modifications produce molecules with vastly different optoelectronic and aggregation properties. This article studies these characteristics with particular focus directed toward the contrast in aggregation-caused quenching (ACQ) properties of 2 compared with the aggregation-induced emission (AIE) properties of 3. The distinct aggregation and photophysical properties of 2 and 3 are delicately exploited using self-assembly with an amphiphilic poloxamer to generate nanoparticles capable of delivering 2 and 3 into cells for biological imaging.

The photoinitiated thiol-ene reaction is emerging as a highly efficient methodology for thioglycoside synthesis. Herein, the radical-mediated hydrothiolation reaction of 4,5-unsaturated saccharides was extended, offering efficient access to C4-position, S-linked glycosides. A diverse range of 4,5-unsaturated saccharides were investigated with high-yields achieved for the thioether products with complete regioselectivity and good diastereoselectivity. 1,2-Ethanedithiol products furnished a thiol-residue suitable for tagging and fluorescent labelling of a disaccharide.

Thiyl radical mediated reactions are of burgeoning importance for organic synthesis. This Feature Article focuses specifically on thioacid- and thioacetate-derived thiyl radicals as versatile intermediates for the synthesis of a diverse range of organic compounds under mild conditions with a high degree of chemo-, regio- and diastereoselectivity. We review recent developments in the field, including novel approaches for radical initiation, strategies for the synthesis of a wide range of functional groups, peptide and glycan diversification, protein labelling and radical dethiocarboxylation. We outline our own contributions to the field over several years, including concomitant strategies to furnish native peptide bonds and discuss the future directions of this field.

The identification and detection of disease-related biomarkers is essential for early clinical diagnosis, evaluating disease progression, and for the development of therapeutics. Possessing the advantages of high sensitivity and selectivity, fluorescent probes have become effective tools for monitoring disease-related active molecules at the cellular level and in vivo. In this review, we describe current fluorescent probes designed for the detection and quantification of key bioactive molecules associated with common diseases, such as organ damage, inflammation, cancers, cardiovascular diseases, and brain disorders. We emphasize the strategies behind the design of fluorescent probes capable of disease biomarker detection and diagnosis and cover some aspects of combined diagnostic/therapeutic strategies based on regulating disease-related molecules. This review concludes with a discussion of the challenges and outlook for fluorescent probes, highlighting future avenues of research that should enable these probes to achieve accurate detection and identification of disease-related biomarkers for biomedical research and clinical applications.

Herein, we present the first examples of amino acid decarboxylation via photochemically activated carbonyl sulfide (COS) elimination of the corresponding thioacids. This method offers a mild approach for the decarboxylation of amino acids, furnishing N-alkyl amino derivatives. The methodology was compatible with amino acids displaying both polar and hydrophobic sidechains and was tolerant towards widely used amino acid-protecting groups. The compatibility of the reaction with continuous-flow conditions demonstrates the scalability of the process.

There remains a critical need for new antibiotics against multi-drug-resistant Gram-negative bacteria, a major global threat that continues to impact mortality rates. Lipoprotein signal peptidase II is an essential enzyme in the lipoprotein biosynthetic pathway of Gram-negative bacteria, making it an attractive target for antibacterial drug discovery. Although natural inhibitors of LspA have been identified, such as the cyclic depsipeptide globomycin, poor stability and production difficulties limit their use in a clinical setting. We harness computational design to generate stable de novo cyclic peptide analogues of globomycin. Only 12 peptides needed to be synthesized and tested to yield potent inhibitors, avoiding costly preparation of large libraries and screening campaigns. The most potent analogues showed comparable or better antimicrobial activity than globomycin in microdilution assays against ESKAPE-E pathogens. This work highlights computational design as a general strategy to combat antibiotic resistance.

The photochemical thiol–ene reaction employing green solvents under continuous-flow conditions is reported as a versatile method for peptide bioconjugation.

The photochemical thiol‐ene reaction is an efficient method for rapid and chemoselective formation of thioether linkages under mild conditions. It has found widespread use in small‐molecule synthesis as well as peptide and protein chemistry. While high‐throughput experimentation provides an invaluable tool for drug discovery, the considerable potential of the thiol‐ene reaction remains unexplored in this context. Herein, we report the development of nanomole‐scale photochemical thiol‐ene chemistry, performed using an automated approach in 1536‐well plates in a cost‐efficient custom reactor. Through careful reaction design and selection of reactants, this chemistry is applied to the lateral diversification of peptidic macrocycles to yield high purity crude mixtures. Selection of the photoinitiator 2,2‐dimethoxy‐2‐phenylacetophenone yields volatile breakdown products, which facilitates removal in vacuo. We demonstrate the use of this approach in late‐stage diversification of peptidic macrocycles with 96 examples averaging 95% conversion to the desired product.

A photochemical acyl thiol-ene reaction can be used to rapidly cyclise fully unprotected peptides bearing both a thioacid and alkene to form peptide thiolactones. This strategy represents the first reported synthesis of peptide thiolactones under radical-mediated conditions.