Discovery of a stable tripeptide targeting the N-domain of CRF1 receptor
| Autor: | Andrew N. Margioris, George Liapakis, Vlasios Karageorgos, George Kokotos, Georgios Leonis, Smaragda Poulaki, George G. Holz, Georgios A. Spyroulias, Eirini Dermitzaki, Katerina Spyridaki, Andreas G. Tzakos, T. Tselios, Androniki D. Kostagianni, Golfo G. Kordopati, Stelios Sakellaris, Ioannis Andreadelis, Dimitris Ntountaniotis, Thomas Mavromoustakos, Konstantinos D. Marousis, Marianna Vanioti, Maria Venihaki, Evgenios Κ. Stylos |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Agonist endocrine system medicine.drug_class Clinical Biochemistry Tripeptide Pharmacology Biochemistry Anxiolytic Receptors Corticotropin-Releasing Hormone Article 03 medical and health sciences Chimera (genetics) Mice Protein Domains Drug Discovery medicine Adipocytes Cyclic AMP Animals Humans Cell Proliferation 030102 biochemistry & molecular biology Chemistry Organic Chemistry HEK 293 cells Rational design Antagonist 030104 developmental biology HEK293 Cells RAW 264.7 Cells Oligopeptides Homeostasis hormones hormone substitutes and hormone antagonists |
| Zdroj: | Amino Acids |
| ISSN: | 1438-2199 |
| Popis: | The corticotropin-releasing factor (CRF) and its CRF1 receptor (CRF(1)R) play a central role in the maintenance of homeostasis. Malfunctioning of the CRF/CRF(1)R unit is associated with several disorders, such as anxiety and depression. Non-peptide CRF(1)R-selective antagonists have been shown to exert anxiolytic and antidepressant effects on experimental animals. However, none of them is in clinical use today because of several side effects, thus demonstrating the need for the development of other more suitable CRF(1)R antagonists. In an effort to develop novel CRF(1)R antagonists we designed, synthesized and chemically characterized two tripeptide analogues of CRF, namely (R)-LMI and (S)-LMI, having their Leu either in R (or D) or in S (or L) configuration, respectively. Their design was based on the crystal structure of the N-extracellular domain (N-domain) of CRF(1)R/CRF complex, using a relevant array of computational methods. Experimental evaluation of the stability of synthetic peptides in human plasma has revealed that (R)-LMI is proteolytically more stable than (S)-LMI. Based on this finding, (R)-LMI was selected for pharmacological characterization. We have found that (R)-LMI is a CRF antagonist, inhibiting (1) the CRF-stimulated accumulation of cAMP in HEK 293 cells expressing the CRF(1)R, (2) the production of interleukins by adipocytes and (3) the proliferation rate of RAW 264.7 cells. (R)-LMI likely blocked agonist actions by interacting with the N-domain of CRF(1)R as suggested by data using a constitutively active chimera of CRF(1)R. We propose that (R)-LMI can be used as an optimal lead compound in the rational design of novel CRF antagonists. |
| Databáze: | OpenAIRE |
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