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

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 aci...

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Bibliographic Details
Published in:Nature biotechnology 1999-06, Vol.17 (6), p.562-567
Main Authors: Nagy, Zoltan A, Falcioni, Fiorenza, Ito, Kouichi, Vidovic, Damir, Belunis, Charles, Campbell, Robert, Berthel, Steven J, Bolin, David R, Gillespie, Paul B, Huby, Nicholas, Olson, Gary L, Sarabu, Ramakanth, Guenot, Jeanmarie, Madison, Vincent, Hammer, Jürgen, Sinigaglia, Francesco, Steinmetz, Michael
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino Acid Substitution
Antigen Presentation - drug effects
Antigen Presentation - immunology
Arthritis, Rheumatoid - immunology
Biological and medical sciences
Biotechnology
Cathepsins - metabolism
Cell Line
Fundamental and applied biological sciences. Psychology
Health. Pharmaceutical industry
HLA-DR Antigens - immunology
HLA-DR Antigens - metabolism
Humans
Hydrogen Bonding
Industrial applications and implications. Economical aspects
Molecular Mimicry
Oligopeptides - chemistry
Oligopeptides - metabolism
Oligopeptides - pharmacology
Other active biomolecules
Production of active biomolecules
Protein Binding
T-Lymphocytes - drug effects
T-Lymphocytes - immunology
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Summary: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.
ISSN:1087-0156
1546-1696
DOI:10.1038/9865