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Abstract Peptide cyclization has dramatic effects on a variety of important properties, enhancing metabolic stability, limiting conformational flexibility, and altering cellular entry and intracellular localization. The hydrophilic, polyfunctional nature of peptides creates chemoselectivity challenges in macrocyclization, especially for natural sequences without biorthogonal handles. Herein, we describe a gaseous sulfonyl chloride derived reagent that achieves amine–amine, amine–phenol, and amine–aniline crosslinking through a minimalist linchpin strategy that affords macrocyclic urea or carbamate products. The cyclization reaction is metal‐mediated and involves a novel application of sulfine species that remains unexplored in aqueous or biological contexts. The aqueous method delivers unique cyclic or bicyclic topologies directly from a variety of natural bioactive peptides without the need for protecting‐group strategies. 

Abstract Maintaining safe and potent pharmaceutical drug levels is often challenging. Multidomain peptides (MDPs) assemble into supramolecular hydrogels with a well-defined, highly porous nanostructure that makes them attractive for drug delivery, yet their ability to extend release is typically limited by rapid drug diffusion. To overcome this challenge, we developed self-assembling boronate ester release (SABER) MDPs capable of engaging in dynamic covalent bonding with payloads containing boronic acids (BAs). As examples, we demonstrate that SABER hydrogels can prolong the release of five BA-containing small-molecule drugs as well as BA-modified insulin and antibodies. Pharmacokinetic studies revealed that SABER hydrogels extended the therapeutic effect of ganfeborole from days to weeks, preventingMycobacterium tuberculosisgrowth better than repeated oral administration in an infection model. Similarly, SABER hydrogels extended insulin activity, maintaining normoglycemia for six days in diabetic mice after a single injection. These results suggest that SABER hydrogels present broad potential for clinical translation. 

We report a minimalist gaseous sulfonyl-chloride-derived reagent for multicomponent bioconjugation with amine, phenol, or aniline reagents to afford urea or carbamate products. With the utilization of a gas-phase reagent for a reaction mediated by metal ions, a variety of biologically relevant molecules, such as saccharide, poly(ethylene glycol), fluorophore, and affinity tag, can be efficiently cross-linked to the N terminus or lysine side-chain amines on natural polypeptides or proteins. 

Here, we demonstrate a fundamentally new reactivity of the silyl enol ether functionality utilizing an in situ generated iodonitrene-like species. The present transformation inserts a nitrogen atom between the silyl enol ether olefinic carbons with the concomitant cleavage of the CC bond. Overall, this facile transformation converts a C-nucleophilic silyl enol ether to the corresponding C-electrophilic N-acyl-N,O-acetal. This unprecedented access to α-amido alkylating agents enables modular derivatization with carbon and heteroatom nucleophiles and the unique late-stage editing of carbon frameworks. The reaction efficiency of this transformation is well correlated with enol ether nucleophilicity as described by the Mayr N scale. Applications presented herein include late-stage nitrogen insertion into carbon skeletons of natural products with previously unattainable regioselectivity as well as modified conditions for 15N labeling of amides and lactams. 

Pyroglutamate is a cyclic N-terminal posttranslational modifica-tion that occurs in both proteins and peptide hormones. The prevalence and biological roles of pyroglutamate are little under-stood, in part due to limited tools to identify, quantify, and ma-nipulate its pyrrolidinone structure. Selective modification of pyroglutamate residues in complex polypeptides may provide unique tools to better understand its biological roles, and to al-low late-stage diversification of biologically active pyrogluta-mate-containing sequences. This work describes a copper-catalyzed N–H cross-coupling of unprotected peptides that is selective for N-terminal pyroglutamate residues. The reaction is operationally simple under mild conditions, and tolerates almost all canonical residues. Mechanistic studies point to a key role for a multidentate copper-binding mode of the extended polypeptide structure in delivering the observed reactivity. The reaction al-lows direct labeling and identification of a pyroglutamate hormone present in porcine intestinal extracts. 

Hybrid materials that combine organic polymers and biomacromolecules offer unique opportunities for precisely controlling 3D chemical environments. Although biological or organic templates have been separately used to control the growth of inorganic nanoclusters, hybrid structures represent a relatively unexplored approach to tailoring nanocluster properties. Here, we demonstrate that a molecularly defined lysozyme–polymer resin material acts as a structural scaffold for the synthesis of copper nanoclusters (CuNCs) with well controlled size distributions. The resulting CuNCs have significantly enhanced fluorescence compared with syntheses based on polymeric or biological templates alone. The synergistic approach described here is appealing for the synthesis of biocompatible fluorescent labels with improved photostability. 

Proximity-induced methodologies for peptide and protein modification have been developed using recognition elements like inhibitors, antibodies, or affinity tags on amino acids. However, the recognition a of saccharides for chemical modification remains widely unexplored. Recent studies exploring boronic acids and their derivatives have shown their alluring capabilities as selective molecular recognition elements for saccharides, providing the first insight into a recognition methodology for this moiety. Herein is described the discovery of catalytic proximity-induced rhodium(II) methodology for covalent modification of glycopeptides using boronic acids as a saccharide recognition element. 

Low-temperature plasma is an emerging approach for the treatment of bacterial infections. Nonchemical treatments such as cold plasma offer potential solutions to antibiotic resistance. We investigated the use of laser-induced graphene as aninexpensive, lightweight, and portable electrode for generating cold plasma. At the same time, the mechanism or molecular mediators of cold plasma-induced antibacterial activity remain poorly understood. This study validates graphene as an efficient structure for producing therapeutic cold plasma, and this study also indicates that ozone is the primary mediator of antibacterial activity in graphene-mediated cold plasmas for bacterial growth under the conditions studied. 

Survival of pediatric AML remains poor despite maximized myelosuppressive therapy. The pneumocystis jiroveci pneumonia (PJP)-treating medication atovaquone (AQ) suppresses oxidative phosphorylation (OXPHOS) and reduces AML burden in patient-derived xenograft (PDX) mouse models, making it an ideal concomitant AML therapy. Poor palatability and limited product formulations have historically limited routine use of AQ in pediatric AML patients. Patients with de novo AML were enrolled at two hospitals. Daily AQ at established PJP dosing was combined with standard AML therapy, based on the Medical Research Council backbone. AQ compliance, adverse events (AEs), ease of administration score (scale: 1 (very difficult)-5 (very easy)) and blood/marrow pharmacokinetics (PK) were collected during Induction 1. Correlative studies assessed AQ-induced apoptosis and effects on OXPHOS. PDX models were treated with AQ. A total of 26 patients enrolled (ages 7.2 months–19.7 years, median 12 years); 24 were evaluable. A total of 14 (58%) and 19 (79%) evaluable patients achieved plasma concentrations above the known anti-leukemia concentration (>10 µM) by day 11 and at the end of Induction, respectively. Seven (29%) patients achieved adequate concentrations for PJP prophylaxis (>40 µM). Mean ease of administration score was 3.8. Correlative studies with AQ in patient samples demonstrated robust apoptosis, OXPHOS suppression, and prolonged survival in PDX models. Combining AQ with chemotherapy for AML appears feasible and safe in pediatric patients during Induction 1 and shows single-agent anti-leukemic effects in PDX models. AQ appears to be an ideal concomitant AML therapeutic but may require intra-patient dose adjustment to achieve concentrations sufficient for PJP prophylaxis.