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Plant-Derived Cyclotides Modulate κ-Opioid Receptor Signaling
Edin Muratspahić1, Nataša Tomašević1, Shahrooz Nasrollahi-Shirazi1,2
1Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
Journal of Natural Products
|July 26, 2021
Summary
Plant-derived cyclotides from ipecacuanha bind and modulate the kappa-opioid receptor (KOR). The cyclotide T20K shows potential for developing new analgesics and multiple sclerosis treatments.
Area of Science:
- Pharmacology
- Natural Products Chemistry
- Neuroscience
Background:
- Cyclotides are stable, plant-derived peptides with emerging roles as G protein-coupled receptor (GPCR) ligands.
- The kappa-opioid receptor (KOR) is a key target for analgesics and multiple sclerosis (MS) therapeutics.
- Identifying novel KOR modulators is crucial for developing treatments with improved side effect profiles.
Purpose of the Study:
- To identify cyclotides that interact with the kappa-opioid receptor (KOR).
- To investigate the functional modulation of KOR signaling by the cyclotide T20K.
- To explore the potential of cyclotides as KOR modulators for therapeutic applications.
Main Methods:
- Screening of plant extracts from *Carapichea ipecacuanha*.
- Pharmacological analysis including binding and functional assays (cAMP assays).
- Bioluminescence resonance energy transfer (BRET) assay to study receptor interactions.
Main Results:
- Cyclotides from *Carapichea ipecacuanha* were identified as KOR ligands.
- [T20K]kalata B1 (T20K) bound to and activated KOR in the low micromolar range.
- T20K demonstrated positive allosteric modulation of KOR with dynorphin A1-13 and U50,488, and negative modulation in BRET assays.
Conclusions:
- This study identifies cyclotides as novel modulators of KOR signaling.
- Plant-derived cyclotides, like T20K, represent a promising avenue for developing KOR-targeted therapeutics.
- Cyclotide-based KOR modulators offer potential for new analgesics and MS treatments.
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