Wednesday, 21 February 2018

Cyclotides Isolated from an Ipecac Root Extract Antagonize the Corticotropin Releasing Factor Type 1 Receptor

Front Pharmacol. 2017 Sep 25;8:616. doi: 10.3389/fphar.2017.00616. eCollection 2017. . Fahradpour M1,2, Keov P3, Tognola C1, Perez-Santamarina E1, McCormick PJ4, Ghassempour A2, Gruber CW1,3. Author information 1 Center for Physiology and Pharmacology, Medical University of ViennaVienna, Austria. 2 Medicinal Plants and Drugs Research Institute, Shahid Beheshti UniversityTehran, Iran. 3 Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, BrisbaneQLD, Australia. 4 School of Veterinary Medicine, University of SurreyGuildford, United Kingdom. Abstract Cyclotides are plant derived, cystine-knot stabilized peptides characterized by their natural abundance, sequence variability and structural plasticity. They are abundantly expressed in Rubiaceae, Psychotrieae in particular. Previously the cyclotide kalata B7 was identified to modulate the human oxytocin and vasopressin G protein-coupled receptors (GPCRs), providing molecular validation of the plants' uterotonic properties and further establishing cyclotides as valuable source for GPCR ligand design. In this study we screened a cyclotide extract derived from the root powder of the South American medicinal plant ipecac (Carapichea ipecacuanha) for its GPCR modulating activity of the corticotropin-releasing factor type 1 receptor (CRF1R). We identified and characterized seven novel cyclotides. One cyclotide, caripe 8, isolated from the most active fraction, was further analyzed and found to antagonize the CRF1R. A nanomolar concentration of this cyclotide (260 nM) reduced CRF potency by ∼4.5-fold. In contrast, caripe 8 did not inhibit forskolin-, or vasopressin-stimulated cAMP responses at the vasopressin V2 receptor, suggesting a CRF1R-specific mode-of-action. These results in conjunction with our previous findings establish cyclotides as modulators of both classes A and B GPCRs. Given the diversity of cyclotides, our data point to other cyclotide-GPCR interactions as potentially important sources of drug-like molecules. KEYWORDS: GPCR; circular peptide; corticotropin-releasing factor; ipecac; pharmacognosy; plant peptides PMID: 29033832 PMCID: PMC5627009 DOI: 10.3389/fphar.2017.00616 Free PMC Article