Analysis of the interaction of insulin-like growth factor I (IGF-I) analogs with the IGF-I receptor and IGF-binding proteins.
Analogs of insulin-like growth factor I (IGF-I) have been prepared by site-directed mutagenesis in order to determine the structural domains of IGF-I required for IGF receptor and IGF-binding protein (IGFBP) binding, and to produce analogs with selective affinity for receptors or IGFBP to determine the physiologic roles of these proteins. Distinct domains of IGF-I are important for maintaining high affinity for the IGF-I receptor and for the various species of IGFBPs. The analogs that selectively bind to the receptor and have reduced affinity for IGFBPs have proved useful in determining the relative importance of IGFBPs in the regulation of the biologic activity of IGF-I. In most cases, analogs with reduced affinity for IGFBP have increased or normal potency compared with IGF-I. These data suggest that binding of IGF-I to IGFBP inhibits its biologic activity. As these analogs are cleared more rapidly after parenteral administration, however, they do not provide a significant advantage over IGF-I for in vivo administration. Analogs with poor affinity for the receptor have also been useful in demonstrating that a given activity of IGF-I is mediated by the type 1 IGF receptor. These studies confirm that the role of these various proteins in IGF-I action is complex, and may be cell specific or tissue-type specific.
Cascieri
M A
MA
Department of Molecular Pharmacology and Biochemistry, Merck Research Laboratories, Rahway, N.J. 07065.
Bayne
M L
ML
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008969:Molecular Sequence Data; D017526:Receptor, IGF Type 1 / Q000378:metabolism*
D002352:Carrier Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1