Τμήμα Χημείας

Discovery of a stable tripeptide targeting the N‑domain of CRF1 receptor

Αγγλικά

The corticotropin-releasing factor (CRF) and its CRF1 receptor (CRF1R) play a central role in the maintenance of homeostasis. Malfunctioning of the CRF/CRF1R unit is associated with several disorders, such as anxiety and depression. Non-peptide
CRF1R-selective antagonists have been shown to exert anxiolytic and antidepressant efects on experimental animals. However, none of them is in clinical use today because of several side efects, thus demonstrating the need for the development
of other more suitable CRF1R antagonists. In an efort to develop novel CRF1R 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) confguration, respectively. Their design was based on the crystal structure of the N-extracellular domain
(N-domain) of CRF1R/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 fnding, (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 CRF1R, (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 CRF1R as suggested by data using a constitutively active chimera of CRF1R. We propose
that (R)-LMI can be used as an optimal lead compound in the rational design of novel CRF antagonists.

2020

G. Liapakis, V. Karageorgos, I. Andreadelis, G. G. Holz, E. Dermitzaki, G. G. Kordopati, E. Κ. Stylos, K. Spyridaki, S. Poulaki, D. Ntountaniotis, S. Sakellaris, M. Vanioti, A. Kostagianni, K. D. Marousis, G. Leonis, G. Kokotos,· M. Venihaki, G. A. Spyroulias, T. Tselios, A. M. A. G. Tzakos, T. Mavromoustakos

Journal of Amino Acids

SPRINGER

52

-

1337-1351

The corticotropin-releasing factor (CRF) and its CRF1 receptor (CRF1R) play a central role in the maintenance of homeostasis. Malfunctioning of the CRF/CRF1R unit is associated with several disorders, such as anxiety and depression. Non-peptide CRF1R-selective antagonists have been shown to exert anxiolytic and antidepressant efects on experimental animals. However, none of them is in clinical use today because of several side efects, thus demonstrating the need for the development of other more suitable CRF1R antagonists. In an efort to develop novel CRF1R 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) confguration, respectively. Their design was based on the crystal structure of the N-extracellular domain (N-domain) of CRF1R/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 fnding, (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 CRF1R, (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 CRF1R as suggested by data using a constitutively active chimera of CRF1R. We propose that (R)-LMI can be used as an optimal lead compound in the rational design of novel CRF antagonists.

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