Bioactive Peptide Design Based on Protein Surface Epitopes
A CYCLIC HEPTAPEPTIDE MIMICS CD4 DOMAIN 1 CC′ LOOP AND INHIBITS CD4 BIOLOGICAL FUNCTION*
- Takashi Satoh,
- James M. Aramini,
- Song Li,
- Thea M. Friedman,
- Jimin Gao,
- Andrea E. Edling,
- Robert Townsend,
- Ute Koch,
- Swati Choksi,
- Markus W. Germann,
- Robert Korngold and
- Ziwei Huang‡
- From the Kimmel Cancer Institute, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
Abstract
The interaction between CD4 and major histocompatibility complex class II proteins provides a critical co-receptor function for the activation of CD4+ T cells implicated in the pathogenesis of a number of autoimmune diseases and transplantation responses. A small synthetic cyclic heptapeptide was designed and shown by high resolution NMR spectroscopy to closely mimic the CD4 domain 1 CC′ surface loop. This peptide effectively blocked stable CD4-major histocompatibility complex class II interaction, possessed significant immunosuppressive activity in vitro and in vivo, and strongly resisted proteolytic degradation. These results demonstrate the therapeutic potential of this peptide as a novel immunosuppressive agent and suggest a general strategy of drug design by using small conformationally constrained peptide mimics of protein surface epitopes to inhibit protein interactions and biological functions.
Footnotes
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↵* This work was supported by the Kimmel Cancer Institute of the Jefferson Medical College, National Institutes of Health Grants AI40081 (to Z. H.) and NS34928 (to R. K.), and National Multiple Sclerosis Society Grant RG2854 (to Z. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ To whom correspondence should be addressed. Tel.: 215-503-4564; Fax: 215-923-2117; E-mail: Z_Huang{at}lac.jci.tju.edu.
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↵1 The abbreviations used are: D1–D4, domains 1–4; MHC, major histocompatibility complex; GVHD, graftversus host disease; Fmoc,N-(9-fluorenyl)methoxycarbonyl; HPLC, high performance liquid chromatography; NOE, nuclear Overhauser effect; MLR, mixed-lymphocyte reaction; Gy, gray; EAE, experimental allergic encephalomyelitis; DOSPER, 1,3-dioleoyloxy-2-(6-carboxyspermyl)-propylamid.
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↵2 T. Satoh, S. Li, J. Gao, R. Korngold, and Z. Huang, manuscript in preparation.
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- Received December 12, 1996.
- Revision received February 26, 1997.
