Fluorescent probes for G-protein-coupled receptor drug discovery

ABSTRACT

Introduction: G-protein-coupled receptors (GPCRs) mediate the effects of approximately 33% of all marketed drugs. The development of tools to study GPCR pharmacology is urgently needed as it can lead to the discovery of safer and more effective medications. Fluorescent GPCR ligands represent highly sensitive and safe small-molecule tools for real-time exploration of the life of the receptor, cellular signaling, and ligand–/receptor–receptor interactions in cellulo and/or in vivo.

Areas covered: This review summarizes relevant information from published literature and provides critical insights into the design of successful small-molecule fluorescent probes for Class A GPCRs as potential major targets for drug development.

Expert opinion: Considering the rapid progress of fluorescence technologies, effective small-molecule fluorescent probes represent valuable pharmacological tools for studying GPCRs. However, the design and development of such probes are challenging, largely due to the low affinity/specificity of the probe for its target, inadequate photophysical properties, extensive non-specific binding, and/or low signal-to-noise ratio. Generally speaking, fluorescent and luminescent small-molecule probes, receptors, and G proteins in combination with FRET and BRET technologies hold great promise for studying kinetic profiles of GPCR signaling.

KEYWORDS:

• Fluorescent probes
• G-protein coupled receptors
• imaging
• drug development

Article highlights

• G-protein coupled receptors (GPCRs) are major targets for drug development.

• Class A (Rhodopsin-like) is the largest class of GPCRs and accounts for nearly 85% of the GPCR genes. It encompasses receptors that are activated by endogenous ligands as well as orphan and olfactory receptors.

• Small-molecule fluorescent probes represent valuable tools for real-time studies in GPCR pharmacology.

• The design of fluorescent GPCR small-molecules is challenging and the development of such probes is limited.

• Fluorescent and luminescent small-molecule probes, receptors, and G proteins in combination with FRET and BRET technologies hold great promise for studying kinetic profiles of GPCR signaling

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors were supported by the Center for Drug Discovery at Northeastern University