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Mn and Zn-Doped Multivariate Metal-Organic Framework as a Metalloimmunological Adjuvant to Promote Protection Against Tuberculosis Infection
No full textA first-in-class vaccine adjuvant delivery system, Mn-ZIF, was developed by incorporating manganese (Mn) into the zinc-containing zeolitic-imidazolate framework-8 (ZIF-8). The mixed metal approach, which allowed for tunable Mn doping, was made possible by including a mild reducing agent into the reaction mixture. This approach allowed up to 50% Mn, with the remaining 50% Zn within the ZIF. This multivariate approach exhibited significantly decreased cytotoxicity compared to ZIF-8. The porous structure of Mn-ZIF enabled the co-delivery of the STING agonist cyclic di-adenosine monophosphate (CDA) through post-synthetic loading, forming CDA@Mn-ZIF. The composite demonstrated enhanced cellular uptake and synergistic activation of the cGAS-STING pathway, producing proinflammatory cytokines and activating antigen-presenting cells (APCs). In a preclinical Mycobacterium tuberculosis (Mtb) model, CDA@Mn-ZIF formulated with the CysVac2 fusion protein elicited a potent antigen-specific T-cell response and significantly reduced the mycobacterial burden in the lungs of infected mice. These findings highlight the potential of CDA@Mn-ZIF as a promising adjuvant for subunit vaccines, offering a novel approach to enhancing vaccine efficacy and protection against infectious diseases such as tuberculosis
Implementation of an Open Chemistry Knowledge Base with a Semantic Wiki
No full textIn this work, a concept for an open chemistry knowledge base was developed to integrate chemical research results into a collaboratively usable platform. To achieve this, we enhanced Semantic MediaWiki (SMW) to support the collection and structured summary of chemical data contained in publications. We implemented tools for capturing chemical structures in machine-readable formats and designed data forms along with a data model to ensure standardized input and organization of research results. These enhancements allow for effective data comparison and contextual analysis within an expandable Wiki environment. The use of the platform was specifically demonstrated by organizing and comparing research in the area of “CO2 reduction in homogeneous photocatalytic systems,” showcasing its potential to significantly enhance the collaborative collection of research outcomes
Synergistic Energy-Harvesting Coumarin Photocages Enabling Lysosomal pH Rescue
No full textLight-triggered molecular tools releasing bioactive actuators with high spatial and temporal control have prompted significant advances in optobiology. Such probes however require high levels of photosensitivity at biocompatible wavelengths to trigger a biological response safely and efficiently. Here, we propose synergistic, multi-chromophoric, water-soluble systems in which quadrupolar antennas sensitize a coumarinyl photocage, delivering a carboxylic acid payload upon one-photon (visible) or two-photon excitation in the biological transparency near-infrared (NIR) window. Strikingly, the molecular design promotes a 50 % increase in photo-cleavage quantum yield, leading to record photosensitivity for NIR-triggered release of acetic acid. We further demonstrated that these molecular tools efficiently rescue impaired lysosomal pH in a genetic cellular model of Parkinson’s disease. These photoactivated tools are therefore promising candidates for the phototherapeutic management of neurodegenerative disease
Ni-Catalyzed Enantioselective Three-Component Reductive Alkylacylation of Enamides
No full textChiral alpha-amino ketones have found extensive applications as functional molecules. A nickel-catalyzed, enantioselective, and fully intermolecular three-component 1,2-alkylacylation of N-acyl enamides has been realized with tertiary alkyl bromides and carboxylic acid-derived electrophiles as the coupling reagents. This reductive coupling strategy is operationally simple, exhibiting broad substrate scope and excellent functional group tolerance using readily available starting materials and allowing rapid access to structurally complex α-amino ketone derivatives in high enantioselectivity. A suitable chiral biimidazoline ligand together with additional chelation of the amide carbonyl group in a Ni alkyl intermediate facilitates the enantioselective control by suppressing the background reaction, accounting for the excellent enantioselectivity. Mechanistic studies indicated intermediacy of radical species
Fragment correlation mass spectrometry enables direct characterization of di-sulfide cleavage pathways of therapeutic peptides
No full textTherapeutic peptides that are connected by disulfide bonds are often difficult to analyze by traditional tandem mass spec-trometry without chemical modification. Using fragment correlation mass spectrometry, we measured 56 pairs of fragment ions from an equimolar (10 µM) mixture of three cyclic peptides, with sequence coverages for octreotide, desmopressin, and the structural analog of desmopressin to be 86%, 100%, and 75%, respectively. In all detected fragment ion pairs, only 20% of the fragments are terminal ions, with most of the measured MS2 signals only made available by fragment correlation mass spectrometry. From the peak volumes in the covariance map, we calculated branching ratios of each disulfide fragmentation pathway, providing direct measures of disulfide fragmentation probabilities without altering analytes’ chemical structures
Topological Insulators for Thermoelectrics: A Perspective from Beneath the Surface
No full textThermoelectric properties of topological insulators have traditionally been examined in the context of their metallic surface states. However, recent studies have begun to unveil intriguing thermoelectric effects emerging from bulk electronic states, which have largely been overlooked in the past. Charge transport phenomena through the bulk are especially important under typical operating conditions of thermoelectric devices, necessitating a comprehensive review of both surface and bulk transport in topological insulators. Here, we review thermoelectric properties that are uniquely observed in topological insulators, placing special emphasis on unconventional phenomena emerging from bulk states. We demonstrate that unusual thermoelectric effects arising from bulk states, such as band inversion-driven warping, can be discerned in experiments using a rather simple analysis of the weighted mobility. We believe that there is still plenty to uncover within the bulk, yet our current understanding can already inspire new strategies for designing and discovering topological insulators for next-generation thermoelectrics
Indole Nucleophile Triggers Mechanistic Divergence in Ni-Photoredox N–Arylation
No full textThis study presents a Ni-photoredox method for indole N-arylation, broadening the range of substrates to include indoles with unprotected C3-positions and base-sensitive groups. Through detailed mechanistic inquiries, a Ni(I/III) mechanism was uncovered, distinct from those commonly proposed for Ni-catalyzed amine, thiol, and alcohol arylation, as well as from the Ni(0/II/III) cycle identified for amide arylation under almost identical conditions. The key finding is the formation of a Ni(I) intermediate bearing the indole nucleophile as a ligand prior to oxidative addition, which is rare for Ni-photoredox carbon-heteroatom coupling and has a profound impact on the reaction kinetics and scope. The pre-coordination of indole renders a more electron-rich Ni(I) intermediate, which broadens the scope by enabling fast reactivity even with challenging electron-rich aryl bromide substrates. Thus, this work highlights the often-overlooked influence of X-type ligands on Ni oxidative addition rates and illustrates yet another mechanistic divergence in Ni-photoredox C–heteroatom couplings
Simulation-guided engineering enables a functional switch in selinadiene synthase towards hydroxylation
No full textEngineering sesquiterpene synthases to form predefined alternative products is a major challenge due to their diversity in cyclisation mechanisms and our limited understanding of how amino acid changes affect the steering of these mechanisms. Here, we use a combination of atomistic simulation and site-directed mutagenesis to engineer a selina-4(15),7(11)-diene synthase (SdS) such that its final reactive carbocation is quenched by a trapped active site water, resulting in the formation of a complex hydroxylated sesquiterpene (selina-4-ol). Initially, the SdS G305E variant produced 20% selina-4-ol. As suggested by modelling of the enzyme-carbocation complex, selina-4-ol production could be further improved by varying the pH, resulting in selina-4-ol becoming the major product (48%) at pH 6.0. We incorporated the SdS G305E variant along with genes from the mevalonate pathway into bacterial BL21(DE3) cells and demonstrated production of selina-4-ol at a scale of 10 mg/L in batch fermentation. These results highlight opportunities for simulation-guided engineering of terpene synthases to produce predefined complex hydroxylated sesquiterpenes
Bent Naphthodithiophenes: Synthesis and Characterisation of Isomeric Fluorophores
No full textThiophene-containing heteroarenes are one of the most well-known classes of π-conjugated building blocks for photoactive molecules. Isomeric naphthodithiophenes (NDTs) are at the forefront of this research area due to their straightforward synthesis and derivatization. Notably, NDT geometries that are bent – such as naphtho[2,1-b:3,4-b’]dithiophene (α-NDT) and naphtho[1,2-b:4,3-b’]dithiophene (β -NDT) – are seldom employed as photoactive small molecules. This report investigates how remote substituents impact the photophysical properties of isomeric α- and β-NDTs. The orientation of the thiophene units plays a critical role in the emission: in the α(OHex)R2 series conjugation from the end-caps to the NDT core is apparent, while in the β(Oi-Pent)R2 series minimal change is observed unless strong electron acceptors, such as β(Oi-Pent)(PhCF3)2, are employed. This push-pull Acceptor–Donor–Acceptor (A–D–A) fluorophore exhibits positive fluorosolvatochromism that correlates with increasing solvent polarity parameter, ET(30). In total, these results highlight how remote substituents are able to modulate the emission of isomeric bent NDTs
Natural Fragment Bond Orbital Method for Inter-Fragment Bonding Interaction Analysis
No full textA complex chemical system is often examined based on their fragments, so fragment-based analysis is the key to chemical understanding. We report the natural fragment bond orbital (NFBO) method for inter-fragment bonding interaction analysis, as an extension to the well-known natural bond orbital method. NFBOs together with their corresponding natural fragment hybrid orbitals (NFHOs) allow us to derive local bonding and anti-bonding orbitals among fragments from the delocalized canonical molecular orbitals. In this paper, we provide the algorithm for finding NFBOs and showcase its application to several chemically interesting systems featuring significant inter-fragment bonding interactions. Through these examples, the NFBO method is shown to be a powerful tool for molecules possessing strong inter-fragment bonding interactions