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Cyclotides isolated from an ipecac root extract antagonize the corticotropin releasing factor type 1 receptor

Farhadpour, M, Keov, P, Tognola, C, Santamarina, EP, McCormick, Peter, Ghassempour, A and Gruber, CW (2017) Cyclotides isolated from an ipecac root extract antagonize the corticotropin releasing factor type 1 receptor Frontiers in Pharmacology, 8, 616.

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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 sources for novel 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 class A and class B GPCRs. Given the diversity of cyclotides, our data point to other cyclotide-GPCR interactions as potentially important sources of drug-like molecules.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Veterinary Medicine
Authors :
Farhadpour, M
Keov, P
Tognola, C
Santamarina, EP
Ghassempour, A
Gruber, CW
Date : 25 September 2017
DOI : 10.3389/fphar.2017.00616
Copyright Disclaimer : © 2017 Farhadpour, Keov, Tognola, Perez Santamarina, McCormick, Ghassempour and Gruber. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Depositing User : Melanie Hughes
Date Deposited : 23 Aug 2017 14:45
Last Modified : 16 Jan 2019 18:55

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