ACS Central Science最新文献

Mass spectrometry imaging (MSI) is a powerful tool for spatially resolved multiomics analysis of tissue samples in clinical research. However, its proteomics application is still limited due to challenges such as low ionization efficiency and signal interference from complex tissue environments. On-tissue mass-tag labeling (OTMT) addresses these limitations using affinity-based imaging agents that incorporate cleavable, highly ionizable reporter groups known as mass-tags (MTs). The majority of existing MTs rely on antibodies as targeting elements and organic moieties as reporter groups. Here, we introduce a new class of MTs featuring small-molecule inhibitors as binding motifs. Specifically, we present PARPi-MT, composed of a photocleavable and luminescent Ru(II)-based reporter and the poly(ADP-ribose) polymerase (PARP) inhibitor Olaparib for the targeted bimodal imaging of PARP1 in H446 xenograft tumor and mouse brain sections, via desorption electrospray ionization (DESI)-MSI and fluorescence microscopy. Using small-molecule inhibitors as binding motifs expands the design versatility and potential applications of OTMT, while overcoming some of the challenges of antibody-based mass-tags. The Ru(II)-based reporter group offers further advantages, including distinct isotopic signatures derived from the metal center and inherent multimodal imaging capabilities.

An Olaparib-based photocleavable and luminescent Ru(II) mass-tag for the targeted bimodal mass spectrometry imaging (MSI) of PARP in tissue samples by DESI-MSI and fluorescence microscopy.

The bioproduction of 1-alkenes is of significant global interest due to their potential as green commodity chemicals and next-generation ‘drop-in’ biofuels. Here, we report an engineering strategy to enhance the catalytic activity and substrate specificity of the membrane-bound metalloenzyme UndB, significantly improving its utility in biocatalytic 1-alkene production. We developed a highly efficient UndB-based cell-free biocatalytic platform for high-yield medium-chain 1-alkene production. This system achieved a 262-fold improvement in UndB activity toward 1-undecene production, with a total turnover of 3412. Through structural analysis of the UndB family of proteins, we engineered UndB by domain-swapping, enhancing its selectivity toward naturally abundant long-chain fatty acids, enabling efficient long-chain 1-alkene production. Our large-scale simulations unveiled a crucial ion-pair network that orchestrates substrate–protein interactions, providing a framework for substrate stabilization. We identified a highly dynamic and functionally pivotal Arg121 residue that governs substrate uptake and stabilization, providing mechanistic insights into UndB’s substrate recognition. Furthermore, simulations revealed that precise modulation of the substrate-binding pocket volume serves as the key determinant of substrate specificity across UndB variants, offering insights into the evolutionary adaptability of the UndB family. Our system achieved 98% 1-alkene yield using only 0.04 mol % catalyst loading under mild conditions, presenting a promising bioproduction strategy.

Engineered cell-free biocatalytic system boosts UndB activity and substrate specificity, enabling high-yield, selective bioproduction of medium- and long-chain 1-alkenes.

With experimental burials, scientists are looking for chemical signposts that could help real-world investigations.

Calcium ion (Ca²⁺) channels play a key role in mediating cellular gene transcription and signal transduction, emerging as intriguing targets for modulating biological functions. Conjugated molecules (CMs) exhibit distinctive advantages of tunable optoelectronic properties, intrinsic bioactivities, and flexible assembly characteristics, providing various opportunities for the regulation of Ca²⁺ channels. In this Outlook, we introduce the CM-based external-light-reliable or -free photodynamic, the first/second near-infrared (NIR-I/II) light-enabled photothermal, and supramolecular regulations of Ca²⁺ channels for modulating biological functions, including cancer and thrombolysis therapy, remote neurostimulation, and glycemic management. On the other hand, the challenges and perspectives on advancing fast response time, multimodal responsiveness, targeted precision, and biosafety are also discussed, clearly mapping out future development trajectories.

Conjugated-molecule-based photodynamic, photothermal, and supramolecular regulations of Ca²⁺ channels were introduced for modulating disease managements and neurostimulations.

This study investigates combined gadolinium and boron neutron capture therapy (GdBNCT) with carbonic anhydrase IX (CA IX) inhibition for mesothelioma treatment using a multifunctional platform (Gd-B-CA-SF). This platform incorporates a carborane cage for BNCT, a Gd complex for GdNCT/MRI, and a sulfamido group for CA IX inhibition. In vitro studies confirmed CA IX inhibition and selective binding of the compound to AB22 mesothelioma cells, with a 10-fold higher boron uptake compared to that in healthy Met-5a mesothelium. The combination of B and Gd in one molecule allows the exploration of potential additional effects coming from the nuclides ¹⁰B and ¹⁵⁷Gd. Irradiation of AB22 cells showed complete tumor regrowth inhibition after treatment with ¹⁵⁷Gd-¹⁰B-CA-SF, an effect strictly related to the presence of ¹⁵⁷Gd and its localization on the cytosolic membrane. In vivo MRI studies confirmed higher accumulation of Gd-B-CA-SF in AB22 tumors in mice, demonstrating effective targeting. In vivo NCT experiments showed reduced tumor growth in ¹⁵⁷Gd-¹⁰B-CA-SF treated mice, confirming the effectiveness of both ¹⁵⁷Gd and ¹⁰B, even at relatively low concentrations. These results demonstrate the translational potential of Gd-B-CA-SF as a theranostic agent for an innovative approach to cancer treatment.

Theranostic Gd-B-CA-SF combines Gd/B-NCT, and carbonic anhydrase inhibition for mesothelioma treatment exploiting the action of α-particles, Auger electrons, and γ-rays and MRI for real time imaging.

Influenza has caused the deadliest pandemics in history, thereby prompting advances in our ability to ensure vigilance at all stages of future outbreaks. Quarantining patients early is crucial when it comes to preventing these outbreaks, but it is challenging with influenza due to presymptomatic transmission. Presymptomatic detection translates into massive screening needs, which necessitate cost-effective tools with access for anyone, anywhere, and at any time. We met these challenges by synthesizing sensors that respond to influenza infections with taste generation by using the tongue as an always-available detector. In doing so, we utilized the virus’s need for neuraminidase cleavage of α-glycosidic bonds to detect its presence in patients. We synthesized N-acetylneuraminic acid-thymol derivatives and chemically tuned them to respond to viral but not bacterial neuraminidase. Viral selectivity was further confirmed via structural analysis and molecular docking. Influenza sensors that respond to viral presence with taste may have unmatched advantages regarding accessibility and cost-effectiveness, including the potential to first-line stratify millions of healthy individuals from flu patients, thereby enabling us to leverage our response armamentarium in future outbreaks.

We describe influenza sensors that generate a taste-based response recognized by patients offering unique advantages in terms of accessibility and cost. These sensors enable large-scale early screening to distinguish healthy individuals from flu patients and improve outbreak control.

Macrocyclic hosts, possessing cyclic structures capable of encapsulating other molecules and ions, have exhibited unique characteristics in biomedical applications. Having preorganized cavities, macrocyclic hosts can monitor, intervene in, and simulate biological processes by complexing with bioactive substances. Additionally, the framework of macrocyclic hosts can exhibit remarkable efficacy in some applications such as transmembrane transport and antimicrobial. In this Outlook, we expressed some of our personal insights on the distinctive aspects of macrocyclic hosts in biomedical applications, highlighting some examples in disease diagnosis and treatment to provide illustrations. We also discussed the future opportunities and challenges of macrocyclic hosts in biomedical applications along with some suggestions on how to overcome these challenges. Considering the progress we have witnessed in the past decade, we believe that the future of this field is very bright.

Macrocyclic hosts, characterized by their preorganized recognition sites and unique frameworks, have greatly advanced the development of precision and personalized biomedicine.

Site-selective modification of peptides and proteins serves as a powerful tool for biological research and therapeutic development. We present a visible-light-driven stereoretentive peptide/protein–nucleotide conjugation via Cys desulfurization, enabling C5-selective coupling with 6-azauracil nucleosides through stable C–C bond formation. Using Mukaiyama reagent (N-alkyl-2-halopyridinium) activation under visible light (400 or 420–430 nm), this method generates configurationally stable Ala radicals while avoiding the detrimental side effects associated with UVA irradiation. The disulfide-compatible system preserves native stereochemistry and accommodates diverse substrates including oligonucleotides, functionalized nucleosides, and drug conjugates in good yields. Biocompatible reductants (NADH/Hantzsch ester) further facilitate conjugation with various radical acceptors under mild conditions. This approach established a versatile platform that enables both precision modification of peptides/proteins and investigation of structure–function relationships in peptides, proteins, and nucleic acids under physiologically relevant conditions.

A visible-light-driven Cys desulfurization allows stereoretentive, site-selective C−C conjugation of peptides/proteins with nucleotides under mild, biocompatible, and disulfide-compatible conditions.

Nature provides access to biological catalysts that can expand the chemical transformations accessible to synthetic chemists. Among these, α-ketoglutarate, non-heme iron-dependent (NHI) enzymes stand out as scalable biocatalysts for catalyzing selective oxidation reactions. Many NHI enzymes require protein engineering to improve their activity, selectivity, or stability. However, the reliance of this strategy on the innate stability of the enzyme can thwart the success of the engineering campaign. Harnessing innately stable enzymes can overcome these challenges and accelerate biocatalyst engineering. Herein, we highlight the use of ancestral sequence reconstruction (ASR) to mine for thermostable enzymes that can serve as superior starting points for protein engineering. In our effort to develop a biocatalytic route to tropolones, we identified an NHI enzyme that demonstrated poor stability, diminished activity at high substrate concentrations, and a limited substrate scope. We compared the in-lab evolution of the modern NHI enzyme and its ancestor, demonstrating the improved evolvability profile of the latter. By engineering the ancestral protein, we accessed variants with enhanced thermostability and expression, increased rates, and a substrate scope broader than those of their modern counterparts. Altogether, this work provides a strategy to rapidly access enzyme backbones that can accelerate engineering of more robust and synthetically useful NHI enzymes.

Ancestral α-ketoglutarate, non-heme iron dependent enzymes provide more robust backbones with enhanced evolvability, thermostability, and activity toward the formation of tropolone scaffolds.

Tunneling control of chemical reactions is treasured as the third reactivity paradigm, next to kinetic and thermodynamic control. However, reports on the successful observation and mechanistic insight into quantum tunneling in conventional heterogeneous catalysis are limited. By using an atomically dispersed palladium catalyst, we now demonstrate room-temperature catalytic hydrogenation dominated by concerted triple hydrogen tunneling. While a large kinetic isotope effect value of ∼2440 is observed in the benzyl aldehyde hydrogenation when both H₂ and solvent (CH₃OH) are deuterated, the use of protic solvent is important to achieve enhanced catalysis. Systematic investigations reveal that, with a protic solvent molecule situated between the catalytic site and aldehyde, the formation of a local hydrogen bond network helps to induce the concerted triple hydrogen tunneling, namely, that two protons transfer from the ligand on the catalytic site to the mediated solvent and the oxygen of C═O on aldehyde, respectively, and the other transfers from Pd on the catalytic site to the carbon of C═O on aldehyde. With the width and height of the potential energy barrier alterable by protic solvents, the hydrogen tunneling probability can be regulated by solvents. Furthermore, far-infrared irradiation is found to enhance the hydrogenation rate.

This work demonstrates a room-temperature catalytic hydrogenation governed by concerted triple hydrogen tunneling, allowing its regulation with hydrogen-bond networks and far-infrared irradiation.