Discovery and validation of novel peptide agonists for G-protein-coupled receptors.
G-protein-coupled receptors (GPCRs) represent an important group of targets for pharmaceutical therapeutics. The completion of the human genome revealed a large number of putative GPCRs. However, the identification of their natural ligands, and especially peptides, suffers from low discovery rates, thus impeding development of therapeutics based on these potential drug targets. We describe the discovery of novel GPCR ligands encrypted in the human proteome. Hundreds of potential peptide ligands were predicted by machine learning algorithms. In vitro screening of selected 33 peptides on a set of 152 GPCRs, including a group of designated orphan receptors, was conducted by intracellular calcium measurements and cAMP assays. The screening revealed eight novel peptides as potential agonists that specifically activated six different receptors in a dose-dependent manner. Most of the peptides showed distinct stimulatory patterns targeted at designated and orphan GPCRs. Further analysis demonstrated a significant in vivo effect for one of the peptides in a mouse inflammation model.
Shemesh
Ronen
R
Compugen Limited, 72 Pinchas Rosen St., Tel Aviv 69512, Israel. ronens@compugen.co.il
Toporik
Amir
A
Levine
Zurit
Z
Hecht
Iris
I
Rotman
Galit
G
Wool
Assaf
A
Dahary
Dvir
D
Gofer
Eyal
E
Kliger
Yossef
Y
Soffer
Michal Ayalon
MA
Rosenberg
Avi
A
Eshel
Dani
D
Cohen
Yossi
Y
D000465:Algorithms; D000818:Animals; D019295:Computational Biology / Q000379:methods; D000242:Cyclic AMP / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007249:Inflammation; D008024:Ligands; D051379:Mice; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D015202:Protein Engineering; D040901:Proteomics / Q000379:methods; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry*
D008024:Ligands; D010455:Peptides; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP