Cyclic Peptide Interleukin 5 Antagonists Mimic CD Turn Recognition Epitope for Receptor  Piotr Ruchala 1,2,*,† Gyorgyi Varadi 1,2,†,‡ Tetsuya Ishino 1,2,§ Jeffery Scibek 1,2,§ Madhushree Bhattacharya 1,2,§ Cecilia Urbina 1,2,§ Donald Van Ryk 1,2, Iain Uings 3 Irwin Chaiken 1,2,§ 1 Department of Medicine, University of Pennsylvania, 522 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104 2 Department of Biochemistry, Drexel University College of Medicine, 11102 New College Building, 245 N. 15th Street, Philadelphia, PA 19102 3 GlaxoSmithkline, Inc., Asthma Cell Biology, Respiratory and Inflammation CEDD, Stevenage SG1 2NY, UK Received 31 March 2003; accepted 7 November 2003 Published online 16 March 2004 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/bip.20001 Abstract: The cyclic peptide AF17121 (Ac-VDECWRIIASHTWFCAEE) that inhibits interleukin 5 (IL-5) function and IL-5 receptor -chain (IL-5R) 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 Correspondence to: Irwin Chaiken; email: imc23@drexel.edu Contract grant sponsor: National Institutes of Health Contract grant number: 2 RO1 AI 40462-06 and 2 RO1 GM55648-04A2 * Current address: Beth Israel Deaconess Medical Center, Har- vard Medical School, Division of Bone & Mineral Metabolism, 330 Brookline Avenue (HIM 944), Boston MA 02215, USA † These authors contributed equally to this work ‡ Current address: Department of Medical Chemistry, Univer- sity of Szeged, H-6720 Szeged, Dom ter 8, Hungary § Current address: Department of Biochemistry and the A. J. Drexel Institute of Basic and Applied Protein Science, Drexel University College of Medicine, 11102 NCB, MS#497, 245 North 15th Street, Philadelphia PA 19102, USA  Current address: Laboratory of Immunoregulation, NIAID, National Institutes of Health, Bldg. 10, Rm. 6A08, Bethesda MD 20892-1876, USA Biopolymers, Vol. 73, 556 –568 (20004) © 20004 Wiley Periodicals, Inc. 556