Discovery of nanomolar ligands for 7-transmembrane G-protein-coupled receptors from a diverse N-(substituted)glycine peptoid library.
Screening a diverse, combinatorial library of ca. 5000 synthetic dimer and trimer N-(substituted)glycine "peptides" yielded novel, high-affinity ligands for 7-transmembrane G-protein-coupled receptors. The peptoid library was efficiently assembled using readily available chemical building blocks. The choice of side chains was biased to resemble known ligands to 7-transmembrane G-protein-coupled receptors. All peptides were screened in solution-phase, competitive radioligand-binding assays. Peptoid trimer CHIR 2279 binds to the alpha 1-adrenergic receptor with a Ki of 5 nM, and trimer CHIR 4531 binds to the mu-opiate receptor with a Ki of 6 nM. This represents the first example of the discovery of high-affinity receptor ligands from a combinatorial library of non-natural chemical entities.
Zuckermann
R N
RN
Chiron Corporation, Emeryville, California 94608.
Martin
E J
EJ
Spellmeyer
D C
DC
Stauber
G B
GB
Shoemaker
K R
KR
Kerr
J M
JM
Figliozzi
G M
GM
Goff
D A
DA
Siani
M A
MA
Simon
R J
RJ
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D016208:Databases, Factual; D004151:Dipeptides / Q000378:metabolism*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism*; D008024:Ligands; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000378:metabolism*; D034444:Peptoids; D011224:Prazosin / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013329:Structure-Activity Relationship
D004151:Dipeptides; D004745:Enkephalins; D008024:Ligands; D009842:Oligopeptides; D034444:Peptoids; D018340:Receptors, Adrenergic, alpha-1; D011956:Receptors, Cell Surface; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C088972:CHIR 2279; C088973:CHIR 4531; D019204:GTP-Binding Proteins; D005998:Glycine; D011224:Prazosin