Wendong Jia

Nanjing University

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Shuo Huang

Nanjing University

Panke Zhang

Nanjing University

Yuqin Wang

Shaanxi Normal University

Shanyu Zhang

Anhui Medical University

Hong‐Yuan Chen

Nanjing University

Liying Wang

National Institute for Parasitic Diseases

Xiaoyu Du

Nanjing University

Yao Liu

Huazhong University of Science and Technology

Shuanghong Yan

Affiliated Hospital of Hangzhou Normal University

Kefan Wang

Nanjing University

Cooperative Institutions

Nanjing University

Sun Yat-sen University

State Key Laboratory of Analytical Chemistry for Life Science

Collaborative Innovation Center of Advanced Microstructures

Shanghai Jiao Tong University

Northwestern Polytechnical University

Huazhong University of Science and Technology

Peking University

Nankai University

Zhejiang University

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Discrimination of Ribonucleoside Mono-, Di-, and Triphosphates Using an Engineered Nanopore

ACS Nano (2022)

Yuqin Wang Pingping Fan Shanyu Zhang Liying Wang Xinyue Li

Ribonucleotides, which widely exist in all living organisms and are essential to both physiological and pathological processes, can naturally appear as ribonucleoside mono-, di-, and triphosphates. Natural ribonucleotides can also dynamically switch between different phosphorylated forms, posing a great challenge for sensing. A specially engineered nanopore sensor is promising for full discrimination of all canonical ribonucleoside mono-, di-, and triphosphates. However, such a demonstration has never been reported, due to the lack of a suitable nanopore sensor that has a sufficient resolution. In this work, we utilized a phenylboronic acid (PBA) modified Mycobacterium smegmatis porin A (MspA) hetero-octamer for ribonucleotide sensing. Twelve types of ribonucleotides, including mono-, di-, and triphosphates of cytidine (CMP, CDP, CTP), uridine (UMP, UDP, UTP), adenosine (AMP, ADP, ATP), and guanosine (GMP, GDP, GTP) were simultaneously discriminated. A machine-learning algorithm was also developed, which achieved a general accuracy of 99.9% for ribonucleotide sensing. This strategy was also further applied to identify ribonucleotide components in ATP tablets and injections. This sensing strategy provides a direct, accurate, easy, and rapid solution to characterize ribonucleotide components in different phosphorylated forms.

Ribonucleotide

Ribonucleoside

Cytidine

Nanopore

Inosine

10.1021/acsnano.2c09662

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Citations (18)

A Nanopore‐Based Saccharide Sensor

Angewandte Chemie International Edition (2022)

Shanyu Zhang Zhenyuan Cao Pingping Fan Yuqin Wang Wendong Jia

Abstract Saccharides play critical roles in many forms of cellular activities. Saccharide structures are however complicated and similar, setting a technical hurdle for direct identification. Nanopores, which are emerging single molecule tools sensitive to minor structural differences between analytes, can be engineered to identity saccharides. A hetero‐octameric Mycobacterium smegmatis porin A nanopore containing a phenylboronic acid was prepared, and was able to clearly identify nine monosaccharide types, including D‐fructose, D‐galactose, D‐mannose, D‐glucose, L‐sorbose, D‐ribose, D‐xylose, L‐rhamnose and N‐acetyl‐D‐galactosamine. Minor structural differences between saccharide epimers can also be distinguished. To assist automatic event classification, a machine learning algorithm was developed, with which a general accuracy score of 0.96 was achieved. This sensing strategy is generally suitable for other saccharide types and may bring new insights to nanopore saccharide sequencing.

Nanopore

Monosaccharide

Rhamnose

10.1002/anie.202203769

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Citations (59)

Allosteric Switching of Calmodulin in a Mycobacterium smegmatis porin A (MspA) Nanopore‐Trap

Angewandte Chemie International Edition (2021)

Yao Liu Tiezheng Pan Kefan Wang Yuqin Wang Shuanghong Yan

Recent developments concerning large protein nanopores suggest a new approach to structure profiling of native folded proteins. In this work, the large vestibule of Mycobacterium smegmatis porin A (MspA) and calmodulin (CaM), a Ca2+ -binding protein, were used in the direct observation of the protein structure. Three conformers, including the Ca2+ -free, Ca2+ -bound, and target peptide-bound states of CaM, were unambiguously distinguished. A disease related mutant, CaM D129G was also discriminated by MspA, revealing how a single amino acid replacement can interfere with the Ca2+ -binding capacity of the whole protein. The binding capacity and aggregation effect of CaM induced by different ions (Mg2+ /Sr2+ /Ba2+ /Ca2+ /Pb2+ /Tb3+ ) were also investigated and the stability of MspA in extreme conditions was evaluated. This work demonstrates the most systematic single-molecule investigation of different allosteric conformers of CaM, acknowledging the high sensing resolution offered by the MspA nanopore trap.

Mycobacterium smegmatis

Porin

Trap (plumbing)

10.1002/anie.202110545

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Citations (33)

A Nanopore Based Molnupiravir Sensor

ACS Sensors (2022)

Wendong Jia Chengzhen Hu Yuqin Wang Panke Zhang Hong‐Yuan Chen

Nucleoside analogues are reagents that resemble the structure of natural nucleosides and are widely applied in antiviral and anticancer therapy. Molnupiravir, a recently reported nucleoside analogue drug, has shown its inhibitory effect against SARS-CoV-2. Rapid tracing of molnupiravir and its metabolites is important in the evaluation of its pharmacology effect, but direct sensing of molnupiravir as a single molecule has not been reported to date. Here, we demonstrate a nanopore-based sensor with which direct sensing of molnupiravir and its two major metabolites β-d-N4-hydroxycytidine and its triphosphate can be achieved simultaneously. In conjunction with a custom machine learning algorithm, an accuracy of 92% was achieved. This sensing strategy may be useful in the current pandemic and is in principle suitable for other nucleoside analogue drugs.

Nanopore

Nucleoside analogue

10.1021/acssensors.2c00447

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Citations (8)

Nanopore Signatures of Nucleoside Drugs

Nano Letters (2023)

Wendong Jia Yusheng Ouyang Shanyu Zhang Xiaoyu Du Panke Zhang

Nucleoside drugs, which are analogues of natural nucleosides, have been widely applied in the clinical treatment of viral infections and cancers. The development of nucleoside drugs, repurposing of existing drugs, and combined use of multiple drug types have made the rapid sensing of nucleoside drugs urgently needed. Nanopores are emerging single-molecule sensors that have high resolution to resolve even minor structural differences between chemical compounds. Here, an engineered Mycobacterium smegmatis porin A hetero-octamer was used to perform general nucleoside drug analysis. Ten nucleoside drugs were simultaneously detected and fully discriminated. An accuracy of >99.9% was consequently reported. This sensing capacity was further demonstrated in direct nanopore analysis of ribavirin buccal tablets, confirming its sensing reliability against complex samples and environments. No sample separation is needed, however, significantly minimizing the complexity of the measurement. This technique may inspire nanopore applications in pharmaceutical production and pharmacokinetics measurements.

Nanopore

Nucleoside analogue

10.1021/acs.nanolett.3c02872

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Citations (8)

A Nanopore‐Based Saccharide Sensor

Angewandte Chemie (2022)

Shanyu Zhang Zhenyuan Cao Pingping Fan Yuqin Wang Wendong Jia

Nanopore

Monosaccharide

Rhamnose

10.1002/ange.202203769

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Citations (9)

Single-Molecule Interconversion between Chiral Configurations of Boronate Esters Observed in a Nanoreactor

ACS Nano (2023)

Xiaoyu Du Shanyu Zhang Liying Wang Yuqin Wang Pingping Fan

Isomers of some chemical compounds may be dynamically interconvertible. Due to a lack of sensing methods with a sufficient resolution, however, direct monitoring of such processes can be difficult. Engineered Mycobacterium smegmatis porin A (MspA) nanopores can be applied as nanoreactors so that chemical reactions can be directly monitored. Here, an MspA modified with a phenylboronic acid (PBA) adapter was prepared and was used to observe dynamic interconversion between chiral configurations of boronate esters, which appears as telegraphic switching on top of nanopore events. The mechanism of this behavior was further confirmed by trials with different halogenated catechols, dopamine, adenosine, 1,2-propanediol, and (2R,3R)-2,3-butanediol, and its generality has been demonstrated. These results suggest that an engineered MspA possesses an exceptional resolution in its monitoring of chemical reaction processes and may inspire the future design of nanopore small-molecule sensors.

Nanoreactor

Mycobacterium smegmatis

Nanopore

Tetrahydrothiophene

Phenylboronic acid

Adapter (computing)

10.1021/acsnano.2c11286

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Citations (12)

Programmable nano-reactors for stochastic sensing

Nature Communications (2021)

Wendong Jia Chengzhen Hu Yuqin Wang Yuming Gu Guang‐Rui Qian

Abstract Chemical reactions of single molecules, caused by rapid formation or breaking of chemical bonds, are difficult to observe even with state-of-the-art instruments. A biological nanopore can be engineered into a single molecule reactor, capable of detecting the binding of a monatomic ion or the transient appearance of chemical intermediates. Pore engineering of this type is however technically challenging, which has significantly restricted further development of this technique. We propose a versatile strategy, “programmable nano-reactors for stochastic sensing” (PNRSS), by which a variety of single molecule reactions of hydrogen peroxide, metal ions, ethylene glycol, glycerol, lactic acid, vitamins, catecholamines or nucleoside analogues can be observed directly. PNRSS presents a refined sensing resolution which can be further enhanced by an artificial intelligence algorithm. Remdesivir, a nucleoside analogue and an investigational anti-viral drug used to treat COVID-19, can be distinguished from its active triphosphate form by PNRSS, suggesting applications in pharmacokinetics or drug screening.

Nanopore

Biomolecule

10.1038/s41467-021-26054-9

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Citations (38)

Identification of Single-Molecule Catecholamine Enantiomers Using a Programmable Nanopore

ACS Nano (2022)

Wendong Jia Chengzhen Hu Yuqin Wang Yao Liu Liying Wang

Enantiomers, chiral isomers with opposite chirality, typically demonstrate differences in their pharmacological activity, metabolism, and toxicity. However, direct discrimination between enantiomers is challenging due to their similar physiochemical properties. Following the strategy of programmable nanoreactors for stochastic sensing (PNRSS), introduction of phenylboronic acid (PBA) to a Mycobacterium smegmatis porin A (MspA) assists in the identification of the enantiomers of norepinephrine and epinephrine. Using a machine learning algorithm, identification of the enantiomers has been achieved with an accuracy of 98.2%. The enantiomeric excess (ee) of a mixture of enantiomeric catecholamines was measured to determine the enantiomeric purity. This sensing strategy is a faster method for the determination of ee values than liquid chromatography-mass spectrometry and is useful as a quality control in the industrial production of enantiomeric drugs.

Enantiomeric excess

10.1021/acsnano.2c01017

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Citations (32)

Simultaneous Identification of Vitamins B1, B3, B5, and B6 by an Engineered Nanopore

Nano Letters (2024)

Yusheng Ouyang Kefan Wang Wendong Jia Panke Zhang Shuo Huang

Vitamin Bs, a group of water-soluble compounds, are essential nutrients for almost all living organisms. However, due to their structural heterogeneity, rapid and simultaneous analysis of multiple vitamin Bs is still challenging. In this paper, it is discovered that a hetero-octameric

Nanopore

Identification

10.1021/acs.nanolett.4c03329

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Citations (1)