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

Mohsen Fahradpour, Peter Keov, Carlotta Tognola, Estela Perez-Santamarina, Peter J. McCormick, Alireza Ghassempour, Christian W. Gruber

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number616
Number of pages14
JournalFrontiers in Pharmacology
Volume8
Issue numberSEP
DOIs
Publication statusPublished - 25 Sep 2017
Externally publishedYes

Keywords

  • Circular peptide
  • Corticotropin-releasing factor
  • GPCR
  • Ipecac
  • Pharmacognosy
  • Plant peptides

Cite this

Fahradpour, M., Keov, P., Tognola, C., Perez-Santamarina, E., McCormick, P. J., Ghassempour, A., & Gruber, C. W. (2017). Cyclotides isolated from an ipecac root extract antagonize the corticotropin releasing factor type 1 receptor. Frontiers in Pharmacology, 8(SEP), [616]. https://doi.org/10.3389/fphar.2017.00616
Fahradpour, Mohsen ; Keov, Peter ; Tognola, Carlotta ; Perez-Santamarina, Estela ; McCormick, Peter J. ; Ghassempour, Alireza ; Gruber, Christian W. / Cyclotides isolated from an ipecac root extract antagonize the corticotropin releasing factor type 1 receptor. In: Frontiers in Pharmacology. 2017 ; Vol. 8, No. SEP.
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Fahradpour, M, Keov, P, Tognola, C, Perez-Santamarina, E, McCormick, PJ, Ghassempour, A & Gruber, CW 2017, 'Cyclotides isolated from an ipecac root extract antagonize the corticotropin releasing factor type 1 receptor' Frontiers in Pharmacology, vol. 8, no. SEP, 616. https://doi.org/10.3389/fphar.2017.00616

Cyclotides isolated from an ipecac root extract antagonize the corticotropin releasing factor type 1 receptor. / Fahradpour, Mohsen; Keov, Peter; Tognola, Carlotta; Perez-Santamarina, Estela; McCormick, Peter J.; Ghassempour, Alireza; Gruber, Christian W.

In: Frontiers in Pharmacology, Vol. 8, No. SEP, 616, 25.09.2017.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Cyclotides isolated from an ipecac root extract antagonize the corticotropin releasing factor type 1 receptor

AU - Fahradpour, Mohsen

AU - Keov, Peter

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AU - McCormick, Peter J.

AU - Ghassempour, Alireza

AU - Gruber, Christian W.

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AB - 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.

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