GRF analogs and fragments: correlation between receptor binding, activity and structure.
GH-releasing activity in vitro was directly correlated with GRF receptor binding affinity for all hGRF analogs examined. hGRF(1-29)-NH2 analogs with Ala15-substitution (for Gly15) displayed 4-5 times higher affinity for the GRF receptor relative to hGRF(1-44)-NH2. Replacement of Gly15 with Sar15 resulted in a dramatic loss of activity and receptor binding. The present data supports the proposal that Ala15-substitution increases receptor affinity, and hence potency, due to increased amphiphilic alpha-helical interactions. Fragments of hGRF, representative of DPP-IV and trypsin-like cleavage, are inactive as a consequence of greatly diminished GRF receptor binding. These results provide a comprehensive analysis of the structural features required for both GRF receptor binding and activation.
Campbell
R M
RM
Department of Animal Science, Hoffmann-La Roche Inc., Nutley, NJ 07110.
Lee
Y
Y
Rivier
J
J
Heimer
E P
EP
Felix
A M
AM
Mowles
T F
TF
D000818:Animals; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D011919:Rats, Inbred Strains; D018013:Receptors, Neuropeptide; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D013329:Structure-Activity Relationship
D010446:Peptide Fragments; D018013:Receptors, Neuropeptide; D017981:Receptors, Neurotransmitter; D018017:Receptors, Pituitary Hormone-Regulating Hormone; C039542:somatocrinin receptor; D013007:Growth Hormone-Releasing Hormone