Design and synthesis of potent cystine-free cyclic hexapeptide agonists at the human urotensin receptor.
[structure: see text] Cyclic hexapeptides, incorporating a dipeptide unit in place of the disulfide bond found in urotensin, were prepared and screened at the human urotensin receptor. The bridging dipeptide unit was found to influence dramatically the affinity for the urotensin receptor. Alanyl-N-methylalanyl and alanylprolyl dipeptide bridges failed to afford active ligands, while the alanyl-alanyl unit yielded a ligand with submicromolar affinity for the urotensin receptor. Further development led to a hexapeptide agonist with nanomolar affinity (2.8 nM).
Foister
Shane
S
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Taylor
Laurie L
LL
Feng
Jin-Jye
JJ
Chen
Wen-Long
WL
Lin
Atsui
A
Cheng
Fong-Chi
FC
Smith
Amos B
AB
Hirschmann
Ralph
R
D000595:Amino Acid Sequence; D001665:Binding Sites; D003553:Cystine / Q000737:chemistry; D004151:Dipeptides / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry*; D014579:Urotensins / Q000819:agonists* / Q000737:chemistry
D004151:Dipeptides; D010456:Peptides, Cyclic; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human; D014579:Urotensins; D003553:Cystine