High affinity type I interleukin 1 receptor antagonists discovered by screening recombinant peptide libraries.
Two families of peptides that specifically bind the extracellular domain of the human type I interleukin I (IL-1) receptor were identified from recombinant peptide display libraries. Peptides from one of these families blocked binding of IL-lalpha to the type I IL-1 receptor with IC50 values of 45-140 microM. Affinity-selective screening of variants of these peptides produced ligands of much higher affinity (IC50 approximately 2 nM). These peptides block IL-1-driven responses in human and monkey cells; they do not bind the human type II IL-1 receptor or the murine type I IL-1 receptor. This is the first example (that we know of) of a high affinity peptide that binds to a cytokine receptor and acts as a cytokine antagonist.
Yanofsky
S D
SD
Department of Molecular Pharmacology, Affymax Research Institute, Palo Alto, CA 94304, USA.
Baldwin
D N
DN
Butler
J H
JH
Holden
F R
FR
Jacobs
J W
JW
Balasubramanian
P
P
Chinn
J P
JP
Cwirla
S E
SE
Peters-Bhatt
E
E
Whitehorn
E A
EA
Tate
E H
EH
Akeson
A
A
Bowlin
T L
TL
Dower
W J
WJ
Barrett
R W
RW
D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D002460:Cell Line; D002478:Cells, Cultured; D017931:DNA Primers; D016208:Databases, Factual; D015232:Dinoprostone / Q000378:metabolism; D066246:ErbB Receptors / Q000096:biosynthesis; D004926:Escherichia coli; D000882:Haplorhini; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011869:Radioligand Assay; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000276:immunology
D017931:DNA Primers; D007375:Interleukin-1; D010455:Peptides; D017472:Receptors, Interleukin-1; D011993:Recombinant Fusion Proteins; D066246:ErbB Receptors; D015232:Dinoprostone