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  1. Article ; Online: Using automated patch clamp electrophysiology platforms in ion channel drug discovery: an industry perspective.

    Rogers, Marc / Obergrussberger, Alison / Kondratskyi, Artem / Fertig, Niels

    Expert opinion on drug discovery

    2024  Volume 19, Issue 5, Page(s) 523–535

    Abstract: Introduction: Automated patch clamp (APC) is now well established as a mature technology for ion channel drug discovery in academia, biotech and pharma companies, and in contract research organizations (CRO), for a variety of applications including ... ...

    Abstract Introduction: Automated patch clamp (APC) is now well established as a mature technology for ion channel drug discovery in academia, biotech and pharma companies, and in contract research organizations (CRO), for a variety of applications including channelopathy research, compound screening, target validation and cardiac safety testing.
    Areas covered: Ion channels are an important class of drugged and approved drug targets. The authors present a review of the current state of ion channel drug discovery along with new and exciting developments in ion channel research involving APC. This includes topics such as native and iPSC-derived cells in ion channel drug discovery, channelopathy research, organellar and biologics in ion channel drug discovery.
    Expert opinion: It is our belief that APC will continue to play a critical role in ion channel drug discovery, not only in 'classical' hit screening, target validation and cardiac safety testing, but extending these applications to include high throughput organellar recordings and optogenetics. In this way, with advancements in APC capabilities and applications, together with high resolution cryo-EM structures, ion channel drug discovery will be re-invigorated, leading to a growing list of ion channel ligands in clinical development.
    MeSH term(s) Humans ; Drug Discovery/methods ; Ion Channels/drug effects ; Animals ; Patch-Clamp Techniques/methods ; Drug Industry/methods ; High-Throughput Screening Assays/methods ; Drug Development/methods ; Induced Pluripotent Stem Cells ; Ligands
    Chemical Substances Ion Channels ; Ligands
    Language English
    Publishing date 2024-03-13
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2259618-5
    ISSN 1746-045X ; 1746-0441
    ISSN (online) 1746-045X
    ISSN 1746-0441
    DOI 10.1080/17460441.2024.2329104
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  2. Article: Functional characterization of SGLT1 using SSM-based electrophysiology: Kinetics of sugar binding and translocation.

    Bazzone, Andre / Zerlotti, Rocco / Barthmes, Maria / Fertig, Niels

    Frontiers in physiology

    2023  Volume 14, Page(s) 1058583

    Abstract: Beside the ongoing efforts to determine structural information, detailed functional studies on transporters are essential to entirely understand the underlying transport mechanisms. We recently found that solid supported membrane-based electrophysiology ( ...

    Abstract Beside the ongoing efforts to determine structural information, detailed functional studies on transporters are essential to entirely understand the underlying transport mechanisms. We recently found that solid supported membrane-based electrophysiology (SSME) enables the measurement of both sugar binding and transport in the Na
    Language English
    Publishing date 2023-02-07
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2023.1058583
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  3. Article ; Online: Automated patch clamp in drug discovery: major breakthroughs and innovation in the last decade.

    Obergrussberger, Alison / Friis, Søren / Brüggemann, Andrea / Fertig, Niels

    Expert opinion on drug discovery

    2020  Volume 16, Issue 1, Page(s) 1–5

    MeSH term(s) Automation ; Drug Discovery/methods ; Drug Discovery/trends ; Humans ; Ion Channels/drug effects ; Ion Channels/metabolism ; Patch-Clamp Techniques/methods ; Patch-Clamp Techniques/trends
    Chemical Substances Ion Channels
    Keywords covid19
    Language English
    Publishing date 2020-07-10
    Publishing country England
    Document type Editorial
    ZDB-ID 2259618-5
    ISSN 1746-045X ; 1746-0441
    ISSN (online) 1746-045X
    ISSN 1746-0441
    DOI 10.1080/17460441.2020.1791079
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  4. Article ; Online: Unraveling the kinetics and pharmacology of human PepT1 using solid supported membrane-based electrophysiology.

    Körner, Alexander / Bazzone, Andre / Wichert, Maximilian / Barthmes, Maria / Dondapati, Srujan Kumar / Fertig, Niels / Kubick, Stefan

    Bioelectrochemistry (Amsterdam, Netherlands)

    2023  Volume 155, Page(s) 108573

    Abstract: The human Peptide Transporter 1 (hPepT1) is known for its broad substrate specificity and its ability to transport (pro-)drugs. Here, we present an in-depth comprehensive study of hPepT1 and its interactions with various substrates via solid supported ... ...

    Abstract The human Peptide Transporter 1 (hPepT1) is known for its broad substrate specificity and its ability to transport (pro-)drugs. Here, we present an in-depth comprehensive study of hPepT1 and its interactions with various substrates via solid supported membrane-based electrophysiology (SSME). Using hPepT1-containing vesicles, we could not identify any peptide induced pre-steady-state currents, indicating that the recorded peak currents reflect steady-state transport. Electrogenic co-transport of H
    MeSH term(s) Humans ; Symporters/metabolism ; Peptide Transporter 1 ; Electrophysiology ; Peptides ; Kinetics
    Chemical Substances Symporters ; Peptide Transporter 1 ; Peptides
    Language English
    Publishing date 2023-09-16
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2010650-6
    ISSN 1878-562X ; 0302-4598 ; 1567-5394
    ISSN (online) 1878-562X
    ISSN 0302-4598 ; 1567-5394
    DOI 10.1016/j.bioelechem.2023.108573
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  5. Article: Automated patch clamp in drug discovery: major breakthroughs and innovation in the last decade

    Obergrussberger, Alison / Friis, Søren / Brüggemann, Andrea / Fertig, Niels

    Expert Opin Drug Discov

    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #638432
    Database COVID19

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  6. Article ; Online: Real-time monitoring β-lactam/β-lactamase inhibitor (BL/BLI) mixture towards the bacteria porin pathway at single molecule level.

    Wang, Jiajun / Fertig, Niels / Ying, Yi-Lun

    Analytical and bioanalytical chemistry

    2019  Volume 411, Issue 19, Page(s) 4831–4837

    Abstract: Multidrug-resistant bacteria are a great concern and a problem that must be addressed. Extended-spectrum β-lactamases are a common defence mechanism of bacteria to make β-lactam (BL) antibiotics ineffective. β-Lactamase inhibitors (BLIs) are consequently ...

    Abstract Multidrug-resistant bacteria are a great concern and a problem that must be addressed. Extended-spectrum β-lactamases are a common defence mechanism of bacteria to make β-lactam (BL) antibiotics ineffective. β-Lactamase inhibitors (BLIs) are consequently designed and are often clinically prescribed with a BL antibiotic to hinder degradation. Current studies focusing on how BL antibiotics or BLIs interact solely with the bacterial outer membrane nanopores (porins) on reaching the periplasmic side using a nanopore-based sensing technique. In electrochemical studies, the bias voltage allows real-time monitoring of BL antibiotics, BLIs and their mixture through the porin pathway at the single-molecule level. Here we consider the most abundant membrane protein from Escherichia coli (i.e. OmpF), purify and reconstitute the membrane protein in an artificial lipid bilayer and then study its ex vivo electrochemical behaviour. We show the piperacillin/tazobactam mixture interacts with OmpF, whereas the substrate interacts under the maximum bandwidth. The power spectrum analysis of the ionic current trace demonstrates the ampicillin/sulbactram mixture requires more energy than ampicillin alone to pass through the porin pathway. Our results demonstrate that clinically relevant combinations (e.g. piperacillin/tazobactam and ampicillin/sulbactam) interact more strongly with OmpF than either the BL antibiotic or the BLI alone. We suggest a quick and relatively cheap screening method to test the ability of BL antibiotics/BLIs to cross the bacterial cellular membrane.
    MeSH term(s) Enzyme Inhibitors/pharmacology ; Microbial Sensitivity Tests ; Porins/drug effects ; beta-Lactamase Inhibitors/pharmacology ; beta-Lactams/antagonists & inhibitors ; beta-Lactams/chemistry
    Chemical Substances Enzyme Inhibitors ; Porins ; beta-Lactamase Inhibitors ; beta-Lactams
    Language English
    Publishing date 2019-03-02
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 201093-8
    ISSN 1618-2650 ; 0016-1152 ; 0372-7920
    ISSN (online) 1618-2650
    ISSN 0016-1152 ; 0372-7920
    DOI 10.1007/s00216-019-01650-3
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    In stock of ZB MED Bonn / Germany

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  7. Article ; Online: Hybrid Cell Analysis System to Assess Structural and Contractile Changes of Human iPSC-Derived Cardiomyocytes for Preclinical Cardiac Risk Evaluation.

    Lickiss, Bettina / Gossmann, Matthias / Linder, Peter / Thomas, Ulrich / Dragicevic, Elena / Lemme, Marta / George, Michael / Fertig, Niels / Stölzle-Feix, Sonja

    Journal of visualized experiments : JoVE

    2022  , Issue 188

    Abstract: Cardiac contractility assessment is of immense importance for the development of new therapeutics and their safe transition into clinical stages. While human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold promise to serve as a ... ...

    Abstract Cardiac contractility assessment is of immense importance for the development of new therapeutics and their safe transition into clinical stages. While human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold promise to serve as a human-relevant model in preclinical phases of drug discovery and safety pharmacology, their maturity is still controversial in the scientific community and under constant development. We present a hybrid contractility and impedance/extracellular field potential (EFP) technology, adding significant pro-maturation features to an industry-standard 96-well platform. The impedance/EFP system monitors cellular functionality in real-time. Besides the beat rate of contractile cells, the electrical impedance spectroscopy readouts detect compound-induced morphological changes like cell density and integrity of the cellular monolayer. In the other component of the hybrid cell analysis system, the cells are cultured on bio-compliant membranes that mimic the mechanical environment of real heart tissue. This physiological environment supports the maturation of hiPSC-CMs in vitro, leading to more adult-like contractile responses including positive inotropic effects after treatment with isoproterenol, S-Bay K8644, or omecamtiv mecarbil. Parameters such as the amplitude of contraction force (mN/mm
    MeSH term(s) Adult ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Myocytes, Cardiac/metabolism ; Myocardial Contraction ; Electrophysiological Phenomena ; Hybrid Cells ; Cells, Cultured
    Language English
    Publishing date 2022-10-20
    Publishing country United States
    Document type Journal Article ; Video-Audio Media ; Research Support, Non-U.S. Gov't
    ZDB-ID 2259946-0
    ISSN 1940-087X ; 1940-087X
    ISSN (online) 1940-087X
    ISSN 1940-087X
    DOI 10.3791/64283
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  8. Article ; Online: A modern automated patch-clamp approach for high throughput electrophysiology recordings in native cardiomyocytes.

    Seibertz, Fitzwilliam / Rapedius, Markus / Fakuade, Funsho E / Tomsits, Philipp / Liutkute, Aiste / Cyganek, Lukas / Becker, Nadine / Majumder, Rupamanjari / Clauß, Sebastian / Fertig, Niels / Voigt, Niels

    Communications biology

    2022  Volume 5, Issue 1, Page(s) 969

    Abstract: Crucial conventional patch-clamp approaches to investigate cellular electrophysiology suffer from low-throughput and require considerable experimenter expertise. Automated patch-clamp (APC) approaches are more experimenter independent and offer high- ... ...

    Abstract Crucial conventional patch-clamp approaches to investigate cellular electrophysiology suffer from low-throughput and require considerable experimenter expertise. Automated patch-clamp (APC) approaches are more experimenter independent and offer high-throughput, but by design are predominantly limited to assays containing small, homogenous cells. In order to enable high-throughput APC assays on larger cells such as native cardiomyocytes isolated from mammalian hearts, we employed a fixed-well APC plate format. A broad range of detailed electrophysiological parameters including action potential, L-type calcium current and basal inward rectifier current were reliably acquired from isolated swine atrial and ventricular cardiomyocytes using APC. Effective pharmacological modulation also indicated that this technique is applicable for drug screening using native cardiomyocyte material. Furthermore, sequential acquisition of multiple parameters from a single cell was successful in a high throughput format, substantially increasing data richness and quantity per experimental run. When appropriately expanded, these protocols will provide a foundation for effective mechanistic and phenotyping studies of human cardiac electrophysiology. Utilizing scarce biopsy samples, regular high throughput characterization of primary cardiomyocytes using APC will facilitate drug development initiatives and personalized treatment strategies for a multitude of cardiac diseases.
    MeSH term(s) Animals ; Calcium ; Electrophysiological Phenomena ; Electrophysiology ; Humans ; Mammals ; Myocytes, Cardiac ; Patch-Clamp Techniques ; Swine
    Chemical Substances Calcium (SY7Q814VUP)
    Language English
    Publishing date 2022-09-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-022-03871-2
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  9. Article: There is no F in APC: Using physiological fluoride-free solutions for high throughput automated patch clamp experiments.

    Rapedius, Markus / Obergrussberger, Alison / Humphries, Edward S A / Scholz, Stephanie / Rinke-Weiss, Ilka / Goetze, Tom A / Brinkwirth, Nina / Rotordam, Maria Giustina / Strassmaier, Tim / Randolph, Aaron / Friis, Søren / Liutkute, Aiste / Seibertz, Fitzwilliam / Voigt, Niels / Fertig, Niels

    Frontiers in molecular neuroscience

    2022  Volume 15, Page(s) 982316

    Abstract: Fluoride has been used in the internal recording solution for manual and automated patch clamp experiments for decades because it helps to improve the seal resistance and promotes longer lasting recordings. In manual patch clamp, fluoride has been used ... ...

    Abstract Fluoride has been used in the internal recording solution for manual and automated patch clamp experiments for decades because it helps to improve the seal resistance and promotes longer lasting recordings. In manual patch clamp, fluoride has been used to record voltage-gated Na (Na
    Language English
    Publishing date 2022-08-22
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2452967-9
    ISSN 1662-5099
    ISSN 1662-5099
    DOI 10.3389/fnmol.2022.982316
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  10. Article ; Online: A high-throughput electrophysiology assay to study the response of PIEZO1 to mechanical stimulation.

    Murciano, Nicoletta / Rotordam, Maria Giustina / Becker, Nadine / Ludlow, Melanie J / Parsonage, Gregory / Darras, Alexis / Kaestner, Lars / Beech, David J / George, Michael / Fertig, Niels / Rapedius, Markus / Brüggemann, Andrea

    The Journal of general physiology

    2023  Volume 155, Issue 12

    Abstract: PIEZO1 channels are mechanically activated cation channels that play a pivotal role in sensing mechanical forces in various cell types. Their dysfunction has been associated with numerous pathophysiological states, including generalized lymphatic ... ...

    Abstract PIEZO1 channels are mechanically activated cation channels that play a pivotal role in sensing mechanical forces in various cell types. Their dysfunction has been associated with numerous pathophysiological states, including generalized lymphatic dysplasia, varicose vein disease, and hereditary xerocytosis. Given their physiological relevance, investigating PIEZO1 is crucial for the pharmaceutical industry, which requires scalable techniques to allow for drug discovery. In this regard, several studies have used high-throughput automated patch clamp (APC) combined with Yoda1, a specific gating modifier of PIEZO1 channels, to explore the function and properties of PIEZO1 in heterologous expression systems, as well as in primary cells. However, a combination of solely mechanical stimulation (M-Stim) and high-throughput APC has not yet been available for the study of PIEZO1 channels. Here, we show that optimization of pipetting parameters of the SyncroPatch 384 coupled with multihole NPC-384 chips enables M-Stim of PIEZO1 channels in high-throughput electrophysiology. We used this approach to explore differences between the response of mouse and human PIEZO1 channels to mechanical and/or chemical stimuli. Our results suggest that applying solutions on top of the cells at elevated pipetting flows is crucial for activating PIEZO1 channels by M-Stim on the SyncroPatch 384. The possibility of comparing and combining mechanical and chemical stimulation in a high-throughput patch clamp assay facilitates investigations on PIEZO1 channels and thereby provides an important experimental tool for drug development.
    MeSH term(s) Humans ; Ion Channels/metabolism ; Mechanotransduction, Cellular/physiology ; High-Throughput Screening Assays ; Electrophysiology
    Chemical Substances Ion Channels ; PIEZO1 protein, human
    Language English
    Publishing date 2023-10-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3118-5
    ISSN 1540-7748 ; 0022-1295
    ISSN (online) 1540-7748
    ISSN 0022-1295
    DOI 10.1085/jgp.202213132
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