Abstract
Genetically-encoded fluorescent sensors have been actively developed over the last few decades and used in live imaging and drug screening. Real-time monitoring of drug action in a specific cellular compartment, organ, or tissue type; the ability to screen at the single-cell resolution; and the elimination of false-positive results caused by low drug bioavailability that is not detected by in vitro testing methods are a few of the obvious benefits of using genetically-encoded fluorescent sensors in drug screening. In combination with high-throughput screening (HTS), some genetically-encoded fluorescent sensors may provide high reproducibility and robustness to assays. We provide a brief overview of successful, perspective, and hopeful attempts at using genetically encoded fluorescent sensors in HTS of modulators of ion channels, Ca2+ homeostasis, GPCR activity, and for screening cytotoxic, anticancer, and anti-parasitic compounds. We discuss the advantages of sensors in whole organism drug screening models and the perspectives of the combination of human disease modeling by CRISPR techniques with genetically encoded fluorescent sensors for drug screening.
Highlights
Assays using genetically encoded fluorescent probes have been extensively developed over the last few decades
We briefly describe some genetically encoded fluorescent assays used for the search of modulators of ion channels, Ca2+ homeostasis, G Protein-Coupled Receptor (GPCR) activity, and for screening cytotoxic, anticancer, and anti-parasitic compounds
Cell Death Signaling Inducers Screening. Another approach in anti-cancer drug discovery is the search for inducers of certain types of cell death, like apoptosis, mitotic catastrophe, or immunogenic cell death, irrespective of drug target
Summary
Assays using genetically encoded fluorescent probes have been extensively developed over the last few decades. Fluorescent biosensors demonstrate low toxicity and do not interfere with normal physiological processes, allowing real-time monitoring of live cells instead of end-point assays on fixed cells or cell extracts They can be used in more complex in vivo systems to test activity and pharmacodynamics of hits and leads. The most commonly used parameter to decide if the assay is suitable for HTS is the Z’-factor, which reflects both dynamic range and data variation It is calculated based on the means (μ) and standard deviations (σ) of positive and negative controls (c+ and c−, respectively): Z. HTS applications require high reproducibility of sensor signal and expression, restricting the number of systems suitable for tests. We discuss the possibilities for using fluorescent sensors for whole-organism HTS
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