Design and evaluation of small peptides mapping the exposed surface of IL-8.
In an effort to determine which regions of IL-8 are involved in interactions with its receptors, eight peptides were designed to correspond to distinct exposed regions of the IL-8 monomer, using the proton NMR-derived structure of the dimer as a basis. The peptides were evaluated singularly, and as equimolar mixtures of two to six peptides, in an IL-8 receptor binding assay and found to have no binding interaction with either alpha or beta IL-8 receptor as single peptides or mixtures of two peptides. In contrast, one of these peptides having the sequence AVLPRSAKEL, which corresponds to the N-terminal 10 amino acid residues of the 77 amino acid form of IL-8, exhibited potent chemotactic activity in human neutrophils. These results indicate that there is no contiguous ligand that can be designed based on the NMR and X-ray determined structure of IL-8 and that there may be multiple receptors responsible for neutrophil activation and chemotaxis.
Thompson
S K
SK
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Veber
D F
DF
Jurewicz
A J
AJ
Peishoff
C E
CE
Lee
J M
JM
White
J R
JR
D000107:Acetylation; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D006801:Humans; D016209:Interleukin-8 / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018375:Neutrophil Activation; D009504:Neutrophils / Q000502:physiology; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D018123:Receptors, Interleukin / Q000378:metabolism*; D023062:Receptors, Interleukin-8A
D015703:Antigens, CD; D016209:Interleukin-8; D010455:Peptides; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A