A Family of Leukemia Inhibitory Factor-Binding Peptides that Can Act as Antagonists When Conjugated to Poly(ethylene glycol)
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- 作者：W. Douglas Fairlie ; Alessandro D. Uboldi ; George J. Hemmings ; Brian J. Smith ; Helene M. Martin ; Phillip O. Morgan ; and Manuel Baca
- 刊名：Biochemistry
- 出版年：2003
- 出版时间：November 18, 2003
- 年：2003
- 卷：42
- 期：45
- 页码：13193 - 13201
- 全文大小：252K
- 年卷期：v.42,no.45(November 18, 2003)
- ISSN：1520-4995
文摘
A panel of six naïve 14-residue random peptide libraries displayed polyvalently on M13 phagewas pooled and sorted against human leukemia inhibitory factor (LIF). After four rounds of selection, asingle large family of peptides with the consensus sequence XCXXXXG(A/S)(D/E)(W/F)WXCF wasfound to bind specifically to LIF. Peptides within this family did not bind related members of theinterleukin-6 family of cytokines, nor to murine LIF that has 80% sequence identity with human LIF. Arepresentative peptide from this family was synthesized and found to bind to LIF with an affinity ofapproximately 300 nM. The phage-displayed form of this peptide was able to compete with the LIFreceptor 
chain (LIFR) for binding to LIF; however, the free synthetic peptide was unable to inhibitLIF-LIFR binding or inhibit LIF bioactivity in vitro. Using a panel of human/murine chimeric LIFmolecules, the peptide-binding site on LIF was mapped to a groove located between the B and the Chelices of the LIF structure, which is distinct from the surfaces involved in binding to receptor. To mimicthe effect of the phage particle and convert the free peptide into an antagonist of LIFR binding, a 40 kDapoly(ethylene glycol) (PEG) moiety was conjugated to the synthetic LIF-binding peptide. This PEG-peptide conjugate was found to be both an antagonist of LIF-LIFR binding and of LIF signaling inengineered Ba/F3 cells expressing LIFR and the gp130 coreceptor.
chain (LIFR) for binding to LIF; however, the free synthetic peptide was unable to inhibitLIF-LIFR binding or inhibit LIF bioactivity in vitro. Using a panel of human/murine chimeric LIFmolecules, the peptide-binding site on LIF was mapped to a groove located between the B and the Chelices of the LIF structure, which is distinct from the surfaces involved in binding to receptor. To mimicthe effect of the phage particle and convert the free peptide into an antagonist of LIFR binding, a 40 kDapoly(ethylene glycol) (PEG) moiety was conjugated to the synthetic LIF-binding peptide. This PEG-peptide conjugate was found to be both an antagonist of LIF-LIFR binding and of LIF signaling inengineered Ba/F3 cells expressing LIFR and the gp130 coreceptor.