Molecular mimics of insulin-like growth factor 1 (IGF-1) for inhibiting IGF-1: IGF-binding protein interactions.
IGF-1 (insulin-like growth factor 1) is a 70-residue protein hormone which has both metabolic and mitogenic activities mediated through IGF-1 binding to cell surface receptors. However, an unrelated class of proteins, the IGF-binding proteins (IGFBPs) also bind IGF-1 in the serum and tissues and block or modulate its activity in vivo. Therefore, inhibitors of the IGFBPs can alter the distribution between free and bound IGF-1 [Loddick, S. A., Liu, X.-J., Lu, Z.-X., Liu, C., Behan, D. P., Chalmers, D. C., Foster, A. C., Vale, W. W., Ling, N., and De Souza, E. B. (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 1894-1898] and potentially affect the distribution of IGF-1 among body tissues. We report here that phage-displayed peptide libraries have yielded a peptide that binds IGFBP-1 and produces IGF-like activity at sub-micromolar concentrations. The 14-residue peptide has an extremely well-defined solution conformation that can aid in the design of smaller, orally active compounds. Interestingly, the peptide structure contains a helix, as does one region of IGF-1 previously implicated in IGFBP binding, yet displays side chains different from those of the IGF-1 helix I. Furthermore, an IGF-1 variant lacking receptor-signaling activity in vitro is shown here to produce IGF-like mitogenic and metabolic activity in vivo. These results suggest that small antagonist mimetics of protein ligands, identified by binding selection to otherwise inhibitory factors, may be useful as indirect agonists for a variety of therapeutic applications.
Lowman
H B
HB
Department of Protein Engineering, Genentech, Inc., South San Francisco, California 94080, USA. hbl@gene.com
Chen
Y M
YM
Skelton
N J
NJ
Mortensen
D L
DL
Tomlinson
E E
EE
Sadick
M D
MD
Robinson
I C
IC
Clark
R G
RG
D000595:Amino Acid Sequence; D000818:Animals; D017104:Bacteriophage M13 / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D017526:Receptor, IGF Type 1 / Q000172:deficiency
D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1