ArticleCells2020
Live-Cell Cardiac-Specific High-Throughput Screening Platform for Drug-Like Molecules that Enhance Ca
Article in Cells, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 28 citations in OpenAlex.
- Development of activators for SERCA2a for heart failure treatments.European journal of medicinal chemistry · 2026Article
- Simultaneous detection of CaMV35S and NOS using fluorescence sensors with dual-emission silver nanoclusters and catalytic hairpin amplification strategy.Mikrochimica acta · 2024Article
- Fluorescence lifetime FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators.Scientific reports · 2023Article
- HTS driven by fluorescence lifetime detection of FRET identifies activators and inhibitors of cardiac myosin.SLAS discovery : advancing life sciences R & D · 2023Article
- FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators.Research square · 2023Article
- New N-aryl-N-alkyl-thiophene-2-carboxamide compound enhances intracellular CaBiophysical journal · 2023Article
- RYR-1-Related Diseases International Research Workshop: From Mechanisms to Treatments Pittsburgh, PA, U.S.A., 21-22 July 2022.Journal of neuromuscular diseases · 2023Article
- A Large-Scale High-Throughput Screen for Modulators of SERCA Activity.Biomolecules · 2022Article
- Synergistic FRET assays for drug discovery targeting RyR2 channels.Journal of molecular and cellular cardiology · 2022Article
- Cardiac calcium regulation in human induced pluripotent stem cell cardiomyocytes: Implications for disease modeling and maturation.Frontiers in cell and developmental biology · 2022Review
- Drug Screening with Genetically Encoded Fluorescent Sensors: Today and Tomorrow.International journal of molecular sciences · 2020Review
- The transmembrane peptide DWORF activates SERCA2a via dual mechanisms.The Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
We engineered a concatenated fluorescent biosensor and dual-wavelength fluorescence lifetime (FLT) detection, to perform high-throughput screening (HTS) in living cells for discovery of potential heart-failure drugs. Heart failure is correlated with insufficient activity of the sarcoplasmic reticulum Ca-pump (SERCA2a), often due to excessive inhibition by phospholamban (PLB), a small transmembrane protein. We sought to discover small molecules that restore SERCA2a activity by disrupting this inhibitory interaction between PLB and SERCA2a. Our approach was to fluorescently tag the two proteins and measure fluorescence resonance energy transfer (FRET) to detect changes in binding or structure of the complex. To optimize sensitivity to these changes, we engineered a biosensor that concatenates the two fluorescently labeled proteins on a single polypeptide chain. This SERCA2a-PLB FRET biosensor construct is functionally active and effective for HTS. By implementing 2-wavelength FLT detection at extremely high speed during primary HTS, we culled fluorescent compounds as false-positive Hits. In pilot screens, we identified Hits that alter the SERCA2a-PLB interaction, and a newly developed secondary calcium uptake assay revealed both activators and inhibitors of Ca-transport. We are implementing this approach for large-scale screens to discover new drug-like modulators of SERCA2a-PLB interactions for heart failure therapeutic development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.