Journal article
Cyclic peptide interleukin 5 antagonists mimic CD turn recognition epitope for receptor alpha
Biopolymers, v 73(5), pp 556-568
05 Apr 2004
PMID: 15048779
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Abstract
The cyclic peptide AF17121 (Ac-VDECWRIIASHTWFCAEE) that inhibits interleukin 5 (IL-5) function and IL-5 receptor alpha-chain (IL-5Ralpha) binding has been derived from recombinant random peptide library screening and follow-up synthetic variation. To better understand the structural basis of its antagonist activity, AF17121 and a series of analogs of the parent peptide were prepared by solid phase peptide synthesis. Sequence variation was focused on the charged residues Asp(2), Glu(3), Arg(6), Glu(17), and Glu(18). Two of those residues, Glu(3) and Arg(6), form an EXXR motif that was found to be common among library-derived IL-5 antagonists. The E and R in the EXXR motif have a proximity similar to charged residues in a previously identified receptor alpha binding region, the beta-strand between the C- and D-helices of human IL-5. Optical biosensor interaction kinetics and cell proliferation assays were used to evaluate the antagonist activities of the purified synthetic peptides, by measuring competition with the highly active single chain IL-5. Analogs in which acidic residues (Asp(2), Glu(3), Glu(17), and Glu(18)) were replaced individually by Ala retained substantial competition activity, with multiple replacements in these residues leading to fractional loss of potency at most. In contrast, R6A analogs had strongly reduced competition activity. The results reveal that the arginine residue is crucial for the IL-5Ralpha binding of AF17121, while the acidic residues are not essential though likely complex-stabilizing particularly in the Asp(2)-Glu(3) region. By CD, AF17121 exhibited mostly disordered structure with evidence for a small beta-sheet content, and replacement of the arginine had no influence on the observed secondary structure of the peptides. The dominance of Arg(6) in AF17121 activity corresponds to previous findings of dominance of the positive charge balance in the antiparallel beta-sheet of IL-5 composed of (88)EERRR(92) in one strand of the CD turn region of IL-5 and with Arg(32) in the neighboring beta-strand. These results argue that AF17121 and related library-derived peptides function by mimicking the CD turn receptor alpha recognition epitope in IL-5 and open the way to small molecule antagonist design.
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Details
- Title
- Cyclic peptide interleukin 5 antagonists mimic CD turn recognition epitope for receptor alpha
- Creators
- Piotr Ruchala - Department of Medicine, University of Pennsylvania, 522 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104, USAGyorgyi VaradiTetsuya IshinoJeffery ScibekMadhushree BhattacharyaCecilia UrbinaDonald Van RykIain UingsIrwin Chaiken
- Publication Details
- Biopolymers, v 73(5), pp 556-568
- Publisher
- Wiley; United States
- Grant note
- 2R01 GM55648-04A2 / NIGMS NIH HHS 2R01 AI40462-06 / NIAID NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000220798700003
- Scopus ID
- 2-s2.0-1842733348
- Other Identifier
- 991014877953504721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Biophysics