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Peptidomimetic compounds that inhibit antigen presentation by autoimmune disease-associated class II major histocompatibility molecules

Nature Biotechnology volume 17, pages 562–567 (1999)Cite this article

Abstract

We have identified a heptapeptide with high affinity to rheumatoid arthritis–associated class II major histocompatibility (MHC) molecules. Using a model of its interaction with the class II binding site, a variety of mimetic substitutions were introduced into the peptide. Several unnatural amino acids and dipeptide mimetics were found to be appropriate substituents and could be combined into compounds with binding affinities comparable to that of the original peptide. Compounds were designed that were several hundred-fold to more than a thousand-fold more potent than the original peptide in inhibiting T-cell responses to processed protein antigens presented by the target MHC molecules. Peptidomimetic compounds of this type could find therapeutic use as MHC-selective antagonists of antigen presentation in the treatment of autoimmune diseases.

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Figure 1: Effect of cathepsin stability and peptidomimetic substitutions on inhibition of antigen presentation.
Figure 2: MHC selectivity of inhibition by different peptidomimetic compounds.

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Acknowledgements

We would like to thank Hongjin Bian, Joel P. Cooper, Donald C. Cox, Diana F. Gaizband, Nan Jiang, Raymond C. Makofske, Margarita Molina, Agostino V. Perrotta, Lucja Orzechowski, Mohan Ramanathan, Joyce I. Toral, Katherine Toth, and Xiaolei Zhang for their expert assistance.

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Author notes

  1. Michael Steinmetz & Zoltan A. Nagy

    Present address: Genome Pharmaceuticals Corporation, 82152, Martinsried/Munich, Germany

Authors and Affiliations

  1. Department of Immunology, Hoffmann-LaRoche, Inc., Nutley, 07110, NJ

    Fiorenza Falcioni, Kouichi Ito, Damir Vidovic & Zoltan A. Nagy

  2. Department of Inflammation and Autoimmune Disease Hoffmann-LaRoche, Inc., Nutley, 07110, NJ

    Charles Belunis, Robert Campbell, Steven J. Berthel, David R. Bolin, Paul B. Gillespie, Nicholas Huby, Gary L. Olson & Ramakanth Sarabu

  3. Department of Physical Chemistry, Hoffmann-LaRoche Inc., Nutley, 07110, NJ

    Jeanmarie Guenot & Vincent Madison

  4. Department of Preclinical Research, Hoffmann-LaRoche Inc., Nutley, 07110, NJ

    Michael Steinmetz

  5. Roche Milano Richerche, Milan, 20132, Italy

    Jürgen Hammer & Francesco Sinigaglia

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  1. Fiorenza Falcioni
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Correspondence to Zoltan A. Nagy.

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Falcioni, F., Ito, K., Vidovic, D. et al. Peptidomimetic compounds that inhibit antigen presentation by autoimmune disease-associated class II major histocompatibility molecules. Nat Biotechnol 17, 562–567 (1999). https://doi.org/10.1038/9865

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