ArticleScientific reports2018
Targeting protein-protein interactions for therapeutic discovery via FRET-based high-throughput screening in living cells.
Article in Scientific reports, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 55 citations in OpenAlex.
- High-throughput screening of FRET-based proteins using a hyperspectral microcapillary array.iScience · 2026Article
- Development of activators for SERCA2a for heart failure treatments.European journal of medicinal chemistry · 2026Article
- SAR-Guided Development of Small-Molecule SERCA2a Activators: Discovery of Potent Indoline, Benzofuran, and Benzodioxole Analogs for Cardiovascular Applications.Journal of medicinal chemistry · 2025Article
- Mechanisms for cardiac calcium pump activation by its substrate and a synthetic allosteric modulator using fluorescence lifetime imaging.PNAS nexus · 2024Article
- Nimesulide, a COX-2 inhibitor, sensitizes pancreatic cancer cells to TRAIL-induced apoptosis by promoting DR5 clustering †.Cancer biology & therapy · 2023Article
- 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
- FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators.Research square · 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
- Broad Tricyclic Ring Inhibitors Block SARS-CoV-2 Spike Function Required for Viral Entry.ACS infectious diseases · 2022Article
- Fluorescence Lifetime Measurement of Prefibrillar Sickle Hemoglobin Oligomers as a Platform for Drug Discovery in Sickle Cell Disease.Biomacromolecules · 2022Article
- Synergistic FRET assays for drug discovery targeting RyR2 channels.Journal of molecular and cellular cardiology · 2022Article
- Stimulation of CaChemMedChem · 2021Article
- Altered SERCA Expression in Breast Cancer.Medicina (Kaunas, Lithuania) · 2021Article
- Protein-Protein Interactions: Insight from Molecular Dynamics Simulations and Nanoparticle Tracking Analysis.Molecules (Basel, Switzerland) · 2021Article
- A multiscale approach for bridging the gap between potency, efficacy, and safety of small molecules directed at membrane proteins.Scientific reports · 2021Article
- Targeting protein-protein interactions in the DNA damage response pathways for cancer chemotherapy.RSC chemical biology · 2021Review
- Soluble Methane Monooxygenase Component Interactions Monitored byBiochemistry · 2021Article
- Potent inhibitors of toxic alpha-synuclein identified via cellular time-resolved FRET biosensors.NPJ Parkinson's disease · 2021Article
- SERCA2a-phospholamban interaction monitored by an interposed circularly permutated green fluorescent protein.American journal of physiology. Heart and circulatory physiology · 2021Article
- Mapping, Structure and Modulation of PPI.Frontiers in chemistry · 2021Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
We have developed a structure-based high-throughput screening (HTS) method, using time-resolved fluorescence resonance energy transfer (TR-FRET) that is sensitive to protein-protein interactions in living cells. The membrane protein complex between the cardiac sarcoplasmic reticulum Ca-ATPase (SERCA2a) and phospholamban (PLB), its Ca-dependent regulator, is a validated therapeutic target for reversing cardiac contractile dysfunction caused by aberrant calcium handling. However, efforts to develop compounds with SERCA2a-PLB specificity have yet to yield an effective drug. We co-expressed GFP-SERCA2a (donor) in the endoplasmic reticulum membrane of HEK293 cells with RFP-PLB (acceptor), and measured FRET using a fluorescence lifetime microplate reader. We screened a small-molecule library and identified 21 compounds (Hits) that changed FRET by >3SD. 10 of these Hits reproducibly alter SERCA2a-PLB structure and function. One compound increases SERCA2a calcium affinity in cardiac membranes but not in skeletal, suggesting that the compound is acting specifically on the SERCA2a-PLB complex, as needed for a drug to mitigate deficient calcium transport in heart failure. The excellent assay quality and correlation between structural and functional assays validate this method for large-scale HTS campaigns. This approach offers a powerful pathway to drug discovery for a wide range of protein-protein interaction targets that were previously considered "undruggable".
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Registered trials
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