Molecular Mimics of Insulin-like Growth Factor 1 (IGF-1) for Inhibiting IGF-1: IGF-Binding Protein Interactions

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• 作者：Henry B. Lowman ; Yvonne M. Chen ; Nicholas J. Skelton ; Deborah L. Mortensen ; Elizabeth E. Tomlinson ; Michael D. Sadick ; Iain C. A. F. Robinson ; and Ross G. Clark
• 刊名：Biochemistry
• 出版年：1998
• 出版时间：June 23, 1998
• 年：1998
• 卷：37
• 期：25
• 页码：8870 - 8878
• 全文大小：121K
• 年卷期：v.37,no.25(June 23, 1998)
• ISSN：1520-4995

文摘

IGF-1 (insulin-like growth factor 1) is a 70-residue proteinhormone which has both metabolicand mitogenic activities mediated through IGF-1 binding to cell surfacereceptors. However, an unrelatedclass of proteins, the IGF-binding proteins (IGFBPs) also bind IGF-1 inthe serum and tissues and blockor modulate its activity in vivo. Therefore, inhibitors of theIGFBPs can alter the distribution betweenfree 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 amongbody tissues. We report here thatphage-displayed peptide libraries have yielded a peptide that bindsIGFBP-1 and produces IGF-like activityat sub-micromolar concentrations. The 14-residue peptide has anextremely well-defined solutionconformation that can aid in the design of smaller, orally activecompounds. Interestingly, the peptidestructure contains a helix, as does one region of IGF-1 previouslyimplicated in IGFBP binding, yet displaysside 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 mitogenicand metabolic activity in vivo.These results suggest that small antagonist mimetics of proteinligands, identified by binding selection tootherwise inhibitory factors, may be useful as indirect agonists for avariety of therapeutic applications.