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Orthogonal Combinatorial Raman Codes Enable Rapid High-Throughput-Out Library Screening of Cell-Targeting Ligands

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Research 2024年第1期2023卷 199-208页

作者： Yuchen Tang Xingxing Zheng Tingjuan Gao China Key laboratory of Pesticide and chemical biology of Ministry of Education College of ChemistryCentral China Normal UniversityWuhan 430079China

High-throughput assays play an important role in the fields of drug discovery,genetic analysis,and clinical diagnostics.Although super-capacity coding strategies may facilitate labeling and detecting large numbers of targets in a single assay,practically,the constructed large-capacity codes have to be decoded with complicated procedures or are lack of survivability under the required reaction conditions.This challenge results in either inaccurate or insufficient decoding outputs.Here,we identified chemical-resistant Raman compounds to build a combinatorial coding system for the high-throughput screening of cell-targeting ligands from a focused 8-mer cyclic peptide library.The accurate in situ decoding results proved the signal,synthetic,and functional orthogonality for this Raman coding strategy.The orthogonal Raman codes allowed for a rapid identification of 63 positive hits at one time,evidencing a high-throughput-out capability in the screening process.We anticipate this orthogonal Raman coding strategy being generalized to enable efficient high-throughput-out screening of more useful ligands for cell targeting and drug discovery.

关键词： enable throughput allowed

Divergent total synthesis of marine meroterpenoids(+)-dysidavarones A–C

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Chinese chemical Letters 2024年第3期35卷 234-238页

作者： Qunlong Zhang Yang Kuang Le Chang Jingyi Kang Bingjian Wang Chuanke Chong Zhaoyong Lu State Key laboratory of Medicinal chemical biology College of PharmacyNankai UniversityTianjin 300350China

Here,we report a concise and divergent enantioselective total synthesis of marine sesquiterpene quinone meroterpenoids(+)-dysidavarones A–C(1–3)using predysidavarone 6 as a key common intermediate.The highly strained and bridged eight-membered carbocycle of predysidavarone 6 was constructed by a one-pot intermolecular alkylation and intramolecular arylation of Wieland–Miescher ketone derivative 11 and benzyl bromide 12.The total synthesis of(+)-dysidavarones A–C(1–3)was achieved from predysidavarone 6 in a divergent manner by a late-stage introduction of the ethoxy group,which reveals the possible source of the ethoxy group within(+)-dysidavarones A–C(1–3)and provides a late-stage modifiable route for the synthesis of dysidavarone analogs for further anti-cancer activity evaluation.

关键词： Total synthesis Natural product Dysidavarones A–C Sesquiterpene quinone Meroterpenoid

Understanding the cooperative effects in the catalysis of homodimeric fluoroacetate dehalogenase

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Science China Chemistry 2024年第7期67卷 2382-2391页

作者： Ke-Wei Chen Jia-Nan Chen Jun Zhang Chao Wang Tian-Yu Sun Yun-Dong Wu Key laboratory of Computational Chemistry and Drug Design State Key Laboratory of Chemical OncogenomicSchool of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhen 518055China Institute of chemical biology Shenzhen Bay LaboratoryShenzhen 518132China College of Chemistry and Molecular Engineering Peking UniversityBeijing 100871China Changping laboratory Beijing 102200China

Fluoroacetate dehalogenases(FAcD),a homodimeric enzyme,catalyzes the conversion of fluoroacetic acid to glycolic acid(GoA).It has been proved that the enzyme has a half-of-the-site reactivity.Namely,its catalytic(C)subunit converts the first substrate to a covalent intermediate;then,the non-catalytic(NC)subunit binds a second substrate and promotes the conversion of the intermediate in the C subunit into the final product.After the release of the product,the C subunit becomes the NC subunit,and the previous NC subunit becomes the C subunit.To elucidate the detailed mechanism behind this cooperative catalysis,we have conducted microsecond-scale MD simulations along the reaction pathway.The simulations indicate that the substrate in the NC subunit induces W185 and Y141 adopting an open conformation in the C subunit.The opening of W185(C)facilitates the entry of catalytic water,enhancing the catalytic activity for product formation,while the opening of Y141(C)creates an unfavorable environment for product binding,promoting its release.An interaction network analysis reveals that the substrate in the NC subunit can induce conformational changes through a conserved water chain at the interface.

关键词： enzyme catalysis molecular dynamics cooperative effect pre-reaction state

Development of a cell-permeable adenine-derived probe for capture of nucleotide-binding proteins in living cells

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Chinese chemical Letters 2024年第3期35卷 243-246页

作者： Lihong Liu Rui Chen Gang Xue Chenzhou Hao Weizhi Weng Zhengying Pan State Key laboratory of chemical Oncogenomics School of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhen 518055China

Adenine is an essential building block of genetic material and a range of coenzymes.chemical probes containing an adenine moiety have been used in kinase profiling studies in cell lysates.Here we report that adenine-derived small-molecule probes with an activated ester reactive group can covalently modify a conserved lysine residue of protein kinases and capture a number of nucleotide-binding proteins within living cells.

关键词： Adenine-derived probe Cell-permeable Lysine residue Protein kinases Nucleotide-binding proteins

Mitochondrial sensitive probe with aggregation-induced emission characteristics for early brain diagnosis of Parkinson’s disease

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Aggregate

Aggregate 2024年第1期5卷 216-227页

作者： Liwen Huang Yutong Zhou Di Jiao Jing Ren Yilin Qi Heping Wang Yang Shi Dan Ding Xue Xue State Key laboratory of Medicinal chemical biology College of PharmacyNankai UniversityTianjinP.R.China State Key laboratory of Medicinal chemical biology Key Laboratory of Bioactive MaterialsMinistry of Educationand College of Life SciencesNankai UniversityTianjinP.R.China

The early diagnosis of Parkinson’s disease(PD)provides opportunities for early intervention to slow the progression of neurological degeneration in patients,particularly as the aging population increases in our society.Among a series of pathological features of PD,mitochondria abnormalities have been identified as central event that occurs at the early stage of PD.However,the method for detecting mitochondrial abnormalities-associated early PD has not been fully developed.We herein report a specifically mitochondrial targeting probe(named TPA-BT-SCP)that is able to characterize mitochondria abnormalities for early diagnosis of PD and monitor PD neurodegenerative progress.The probe is an aggregation-induced emission(AIE)probe with a strong positive charge,a 3D distorted molecular structure,and a separated HOMO-LUMO distribution,designed with unique molecular design guidelines.Our research demonstrated that TPA-BT-SCP could emit stable and strong fluorescence,and rapidly accumulate in mitochondria due to the negative charge.After intranasal administration of 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced PD mice,TPA-BT-SCP successfully bypassed the blood−brain barrier to light up the brain,allowing the grading of PD severity based on its high sensitivity.Taken together,this work develops a novel AIE probe that exhibits dramatically high sensitivity to mitochondrial changes and enables noninvasive diagnosis of early PD in the brain.

关键词： aggregation-induced emission early diagnosis Parkinson’s disease

Monitoring of Cell Membrane Microenvironment Based on DNA Nanodevices

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chemical Research in Chinese Universities 2024年第2期40卷 255-267页

作者： NAN Hexin CAI Ming KUANG Shi NIE Zhou State Key laboratory of Chemo/Biosensing and Chemometrics College of Chemistry and Chemical EngineeringHunan Provincial Key Laboratory of Biomacromolecular Chemical BiologyHunan UniversityChangsha410082P.R.China

The cell membrane is a critical barrier for cellular homeostasis,integral to signaling and intercellular communication,and vital for understanding cellular functions and disease mechanisms.Investigating its microenvironment is crucial for uncovering the molecular basis of physiological and pathological processes associated with the cell membrane,driving the development of bioanalytical toolkits capable of dynamically monitoring the cell surface microenvironment.With the continuous advancement of functional nucleic acids and dynamic DNA nanotechnology,DNA nanodevices with controllable nanosized geometry,specific molecular recognition,and selective membrane-localization properties offer a versatile platform for probing the cell membrane microenvironment.In this review,we summarize the current biosensing and membrane-anchoring mechanisms of DNA nanodevices and highlight their use in studying key cell membrane events,including membrane lipid dynamics,transmembrane transport,receptor dimerization,and signal transduction.Furthermore,we discuss the challenges and potential future applications of DNA nanodevices in advancing cell membrane biology research and biomedical applications.

关键词： DNA nanodevice Cell membrane Cellular micro-environment Monitoring

Multistep continuous flow synthesis of Erlotinib

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Chinese chemical Letters 2024年第4期35卷 371-375页

作者： Hui Jin Qin Cai Peiwen Liu Yan Chen Derong Wang Weiping Zhu Yufang Xu Xuhong Qian State Key laboratory of Bioreactor Engineering Shanghai Key Laboratory of Chemical BiologySchool of PharmacyEast China University of Science and TechnologyShanghai 200237China

Erlotinib is an orally administered, highly effective, specific epidermal growth factor receptor tyrosine kinase inhibitor, used to treat non-small cell lung cancer and pancreatic cancer. The traditional synthetic methods for Erlotinib exhibit long reaction time and safety concern. Herein, we describe a novel five-step route for the synthesis of Erlotinib in flow. These five steps comprise etherification, nitration, reduction,addition and cyclization reactions. All steps were optimized and converted to continuous flow process,which drastically reduces the reaction time and considerably improves the process safety as well as the total yield. Enabled by five continuous flow units, Erlotinib is efficiently afforded with an E-factor of 38,an overall yield of 83%, and a total residence time of 25.1 min. Majority steps in this process have been optimized for quantitative conversion, which offers the possibility of telescoping the entire process.

关键词： Erlotinib Continuous flow synthesis Microchannel flow reactor Process optimization Continuous nitration Continuous hydrogenation

Activatable photoacoustic bioprobe for visual detection of aging in vivo

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Chinese chemical Letters 2024年第4期35卷 324-329页

作者： Zihong Li Jie Cheng Ping Huang Guoliang Wu Weiying Lin Institute of Optical Materials and chemical biology Guangxi Key Laboratory of Electrochemical Energy MaterialsSchool of Chemistry and Chemical EngineeringGuangxi UniversityNanning 530004China

Aging is a natural physiological process with various challenges, related to the loss of homeostasis within the organism, which is not a disease, but a significantly strong risk factor for multiple diseases, including myocardial infarction, stroke, some age-related cancers, macular degeneration, osteoarthritis, neurodegeneration, and many others. In the body, the main manifestation of aging is cellular aging, which exists within tissues and has a local or global impact on tissue function. However, the lack of effective aging detection tools has always been an issue that cannot be ignored in the field of aging research. Therefore,it is necessary to construct a non-invasive tool for in vivo detection of aging. Here, we show that the photoacoustic probe(LGAL), which has peak excitation and emission wavelengths in the near-infrared optical window, binds in vivo and at high contrast to the hallmark of aging, and allows for the microscopic imaging of aging through the intact mice. Firstly, this tool LGAL has been successfully applied to detect senescence in cells, displaying stronger photoacoustic signals than normal cells. Then, by using the photoacoustic probe, the blood vessels and tissues inside the mice can be visualized. Young and elderly mice exhibit varying intensities of photoacoustic signals, marking the first time a probe has been used to explore the aging of blood vessels and tissues inside the mice. Finally, we monitored the changes in the degree of aging during tumor treatment under photoacoustic(PA) imaging for the first time. As the treatment time increased, the degree of aging of the tumor gradually deepened. We expect the powerful tool could be a noninvasive and powerful tool for the study of aging biology.

关键词： Near-infrared Photoacoustic Aging Senescence Tumor Sa-β-gal

Evaluating the tumor stratification with a lysosomal pH sensitive-probe by fluorescence lifetime imaging

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Chinese chemical Letters 2024年第3期35卷 262-267页

作者： Jun Yan Xing Liang Qian Zhang Luolin Wang Weiying Lin Guangxi Key laboratory of Electrochemical Energy Materials Institute of Optical Materials and Chemical BiologySchool of Chemistry and Chemical EngineeringGuangxi UniversityNanning 530004China

Owing to the anaerobic metabolism in the tumor,abundant acidic metabolites are produced and accumulated in the cells.Therefore,the cells in different tumor layers are directly linked to the pH micro-environment.Nevertheless,due to the lack of robust tools,the high-efficient evaluation of the acidic micro-environment of tumor stratification faces the challenge of accurate diagnosis.We designed a new pH sensitive fluorescent lifetime probe target to lysosomes.As we expected,the fluorescence lifetime of PLN possesses a good linear fit to the pH value,which could detect the pH change at a single lysosome level in real time,and then evaluate the different acidity of tumor stratification.The probe PLN is successfully used to evaluate the tumor stratification by fluorescence lifetime imaging microscopy(FLIM)for the first time,which is of great significance in the preoperative diagnosis of clinical tumor treatment or evaluation of drug delivery effect.

关键词： FLIM pH Fluorescence imaging Lysosome Tumor imaging