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与Mona Minkara的对话

A Conversation with Mona Minkara

作者：Julie M. Nyman;

DOI：https://doi.org/10.1021/acscentsci.3c01101

发表时间：2023年

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摘要

这位计算化学家和教授谈论了自己的盲目经历，并倡导其他残疾研究者。

Abstract

This computational chemist and professor discusses being blind and advocating for other researchers with disabilities.

Modular Chemical Construction of IgG-like Mono- and Bispecific Synthetic Antibodies (SynAbs)

In recent years there has been rising interest in the field of protein–protein conjugation, especially related to bispecific antibodies (bsAbs) and their therapeutic applications. These constructs contain two paratopes capable of binding two distinct epitopes on target molecules and are thus able to perform complex biological functions (mechanisms of action) not available to monospecific mAbs. Traditionally these bsAbs have been constructed through protein engineering, but recently chemical methods for their construction have started to (re)emerge. While these have been shown to offer increased modularity, speed, and for some methods even the inherent capacity for further functionalization (e.g., with small molecule cargo), most of these approaches lacked the ability to include a fragment crystallizable (Fc) modality. The Fc component of IgG antibodies offers effector function and increased half-life. Here we report a first-in-class disulfide rebridging and click-chemistry-based method for the generation of Fc-containing, IgG-like mono- and bispecific antibodies. These are in the FcZ-(FabX)-FabY format, i.e., two distinct Fabs and an Fc, potentially all from different antibodies, attached in a homogeneous and covalent manner. We have dubbed these molecules synthetic antibodies (SynAbs). We have constructed a T cell-engager (TCE) SynAb, FcCD20-(FabHER2)-FabCD3, and have confirmed that it exhibits the expected biological functions, including the ability to kill HER2+ target cells in a coculture assay with T cells.

引用量：0发表时间：2023年
Real-Time Monitoring of the Level and Activity of Intracellular Glutathione in Live Cells at Atomic Resolution by19F-NMR

Visualization and quantification of important biomolecules like glutathione (GSH) in live cells are highly important. The existing methods are mostly from optical detection and lack of atomic resolution on the activity of GSH. Here, we present a sensitive 19F-NMR method to quantify real-time variations of GSH in live cells in a reversible manner. This NMR method prevents extracellular leakage and irreversible consumption of intracellular GSH during the detection. The high performance of the reactive 19F-probe enables accurate determination of intracellular GSH content at atomic resolution, from which information on GSH variations with respect to the extracellular and intracellular conditions can be inferred. In addition, we demonstrate the applicability of this NMR method to quantify the GSH levels between different live cell lines and to disclose the distinct differences between the intracellular environment and cell lysates. We foresee the application of 19F-NMR to monitor real-time variations of intracellular GSH levels in relation to GSH-involved central cellular processes.

引用量：0发表时间：2023年
Natural Coumarin Isomers with Dramatically Different AIE Properties: Mechanism and Application

Aggregation-induced emission luminogens (AIEgens) are of great importance in optoelectronics and biomedical fields. However, the popular design philosophy by combining rotors with traditional fluorophores limits the imagination and structural diversity of AIEgens. Inspired by the fluorescent roots of the medicinal plant Toddalia asiatica, we discovered two unconventional rotor-free AIEgens, 5-methoxyseselin (5-MOS) and 6-methoxyseselin (6-MOS). Interestingly, a slight structural difference of the coumarin isomers leads to completely contrary fluorescent properties upon aggregation in aqueous media. Further mechanism investigation indicates that 5-MOS forms different extents of aggregates with the assistance of protonic solvents, leading to electron/energy transfer, which is responsible for its unique AIE feature, i.e., reduced emission in aqueous media but enhanced emission in crystal. Meanwhile, for 6-MOS, the conventional restriction of the intramolecular motion (RIM) mechanism is responsible for its AIE feature. More interestingly, the unique water-sensitive fluorescence property of 5-MOS enables its successful application for wash-free mitochondria imaging. This work not only demonstrates an ingenious tactic to seek new AIEgens from natural fluorescent species but also benefits the structure design and application exploration of next-generation AIEgens.

引用量：0发表时间：2023年
Multivariate Porous Aromatic Frameworks with High Porosity and Hierarchical Structures for Enzyme Immobilization

As materials with permanently porous structures and readily modifying availability, porous aromatic frameworks (PAFs) are considered as promising porous materials with versatile functionality. Currently the designable synthesis of PAFs with the desired surface area and pore size is still a challenge, and instead kinetically irreversible coupling reactions for PAFs synthesis has resulted in the unpredictable connection of building units. Herein, a series of PAFs with highly porous and hierarchical structures were successfully synthesized through a multivariate inspired strategy, where multiple building units with various topologies and sizes were selected for PAFs synthesis. All the PAFs synthesized through this strategy possessed hierarchical structures and high specific surface areas at the same time. Encouraged by their high surface area and hierarchical structures, we loaded lipase onto one of the multivariate PAFs. The enzyme loading content of the obtained lipase@PAF-147 was as high as 1456 mg g–1, which surpassed any other currently reported enzyme loading materials. The lipase@PAF-147 also exhibited favorable catalytic activity and stability to a model reaction of p-nitrophenyl caprylate (p-NPC) hydrolysis. This multivariate strategy inspired synthetic method broadens the selection of building units for PAFs design and opens a new avenue for the design of functional porous materials.

引用量：0发表时间：2023年
Proximity-Induced Nucleic Acid Degrader (PINAD) Approach to Targeted RNA Degradation Using Small Molecules

Nature has evolved intricate machinery to target and degrade RNA, and some of these molecular mechanisms can be adapted for therapeutic use. Small interfering RNAs and RNase H-inducing oligonucleotides have yielded therapeutic agents against diseases that cannot be tackled using protein-centered approaches. Because these therapeutic agents are nucleic acid-based, they have several inherent drawbacks which include poor cellular uptake and stability. Here we report a new approach to target and degrade RNA using small molecules, proximity-induced nucleic acid degrader (PINAD). We have utilized this strategy to design two families of RNA degraders which target two different RNA structures within the genome of SARS-CoV-2: G-quadruplexes and the betacoronaviral pseudoknot. We demonstrate that these novel molecules degrade their targets using in vitro, in cellulo, and in vivo SARS-CoV-2 infection models. Our strategy allows any RNA binding small molecule to be converted into a degrader, empowering RNA binders that are not potent enough to exert a phenotypic effect on their own. PINAD raises the possibility of targeting and destroying any disease-related RNA species, which can greatly expand the space of druggable targets and diseases.

引用量：0发表时间：2023年
Rapid and Highly Stable Membrane Reconstitution by LAiR Enables the Study of Physiological Integral Membrane Protein Functions

Functional reintegration into lipid environments represents a major challenge for in vitro investigation of integral membrane proteins (IMPs). Here, we report a new approach, termed LMNG Auto-insertion Reintegration (LAiR), for reintegration of IMPs into lipid bilayers within minutes. The resulting proteoliposomes displayed an unprecedented capability to maintain proton gradients and long-term stability. LAiR allowed for monitoring catalysis of a membrane-bound, physiologically relevant polyisoprenoid quinone substrate by Escherichia coli cytochromes bo3 (cbo3) and bd (cbd) under control of the proton motive force. LAiR also facilitated bulk-phase detection and physiological assessment of the “proton leak” in cbo3, a controversial catalytic state that previously was only approachable at the single-molecule level. LAiR maintained the multisubunit integrity and higher-order oligomeric states of the delicate mammalian F-ATP synthase. Given that LAiR can be applied to both liposomes and planar membrane bilayers and is compatible with IMPs and lipids from prokaryotic and eukaryotic sources, we anticipate LAiR to be applied broadly across basic research, pharmaceutical applications, and biotechnology.

引用量：0发表时间：2023年
Biocompatible Lysine Protecting Groups for the Chemoenzymatic Synthesis of K48/K63 Heterotypic and Branched Ubiquitin Chains

The elucidation of emerging biological functions of heterotypic and branched ubiquitin (Ub) chains requires new strategies for their preparation with defined lengths and connectivity. While in vitro enzymatic assembly using expressed E1-activating and E2-conjugating enzymes can deliver homotypic chains, the synthesis of branched chains typically requires extensive mutations of lysines or other sequence modifications. The combination of K48- and K63-biased E2-conjugating enzymes and two new carbamate protecting groups─pyridoxal 5′-phosphate (PLP)-cleavable aminobutanamide carbamate (Abac group) and periodate-cleavable aminobutanol carbamate (Aboc group)─provides a strategy for the synthesis of heterotypic and branched Ub trimers, tetramers, and pentamers. The Abac- and Aboc-protected lysines are readily prepared and incorporated into synthetic ubiquitin monomers. As these masking groups contain a basic amine, they preserve the overall charge and properties of the Ub structure, facilitating folding and enzymatic conjugations. These protecting groups can be chemoselectively removed from folded Ub chains and monomers by buffered solutions of PLP or NaIO4. Through the incorporation of a cleavable C-terminal His-tag on the Ub acceptor, the entire process of chain building, iterative Abac deprotections, and global Aboc cleavage can be conducted on a resin support, obviating the need for handling and purification of the intermediate oligomers. Simple modulation of the Ub monomers affords various K48/K63 branched chains, including tetramers and pentamers not previously accessible by synthetic or biochemical methods.

引用量：0发表时间：2023年
How Segmental Dynamics and Mesh Confinement Determine the Selective Diffusivity of Molecules in Cross-Linked Dense Polymer Networks

The diffusion of molecules (“penetrants”) of variable size, shape, and chemistry through dense cross-linked polymer networks is a fundamental scientific problem broadly relevant in materials, polymer, physical, and biological chemistry. Relevant applications include separation membranes, barrier materials, drug delivery, and nanofiltration. A major open question is the relationship between transport, thermodynamic state, and penetrant and polymer chemical structure. Here we combine experiment, simulation, and theory to unravel these competing effects on penetrant transport in rubbery and supercooled polymer permanent networks over a wide range of cross-link densities, size ratios, and temperatures. The crucial importance of the coupling of local penetrant hopping to polymer structural relaxation and the secondary importance of mesh confinement effects are established. Network cross-links strongly slow down nm-scale polymer relaxation, which greatly retards the activated penetrant diffusion. The demonstrated good agreement between experiment, simulation, and theory provides strong support for the size ratio (penetrant diameter to the polymer Kuhn length) as a key variable and the usefulness of coarse-grained simulation and theoretical models that average over Angstrom scale structure. The developed theory provides an understanding of the physical processes underlying the behaviors observed in experiment and simulation and suggests new strategies for enhancing selective polymer membrane design.

引用量：0发表时间：2023年
A Simple yet Efficient Hydrophilic Phenanthroline-Based Ligand for Selective Am(III) Separation under High Acidity

Highly selective hydrophilic ligands were believed to be an efficient way to overcome the massive amount of hazardous organic solvent used in the liquid–liquid extraction process and stood as a new frontier in the Lns(III)/Ans(III) partition. Current reported hydrophilic ligands suffer from harsh preparation conditions, inferior extraction performances, limited available chemical structures, and inability to carry out extraction under high acidity. In this article, we report a simple yet efficient carboxylic group modified phenanthroline-diimide ligand which displayed unexpected Lns(III)/Ans(III) and Ans(III)/Ans(III) separation capabilities in 1.5 M HNO3. Unique dimeric architectures for Eu(III) complexes were observed, which could be the origin of the outperforming selectivity and acid resistance. We believe this crystal engineering approach could inspire a renaissance in searching for new functional groups and coordination modes for efficient, high-acid-tolerance Lns(III)/Ans(III) separation ligands.

引用量：0发表时间：2023年

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与Mona Minkara的对话

A Conversation with Mona Minkara

摘要

Abstract

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