Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions

Timo Burster, Viviana Marin-Esteban, Bernhard O Boehm, Shannon Dunn, Olaf Rotzschke, Kirsten Falk, Ekkehard Weber, Steven H L Verhelst, Hubert Kalbacher, Christoph Driessen

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Multiple Sclerosis (MS) is considered to be a T cell-mediated autoimmune disease. An attractive strategy to prevent activation of autoaggressive T cells in MS, is the use of altered peptide ligands (APL), which bind to major histocompatibility complex class II (MHC II) molecules. To be of clinical use, APL must be capable of resisting hostile environments including the proteolytic machinery of antigen presenting cells (APC). The current design of APL relies on cost- and labour-intensive strategies. To overcome these major drawbacks, we used a deductive approach which involved modifying proteolytic cleavage sites in APL. Cleavage site-directed amino acid substitution of the autoantigen myelin basic protein (MBP) resulted in lysosomal protease-resistant, high-affinity binding peptides. In addition, these peptides mitigated T cell activation in a similar fashion as conventional APL. The strategy outlined allows the development of protease-resistant APL and provides a universal design strategy to improve peptide-based immunotherapeutics.

Original languageEnglish
Pages (from-to)1514-23
Number of pages10
JournalBiochemical Pharmacology
Volume74
Issue number10
DOIs
Publication statusPublished - Nov 15 2007
Externally publishedYes

Fingerprint

Myelin Basic Protein
Amino Acid Substitution
Peptide Hydrolases
Substitution reactions
Amino Acids
Peptides
Ligands
T-cells
T-Lymphocytes
Multiple Sclerosis
Chemical activation
Peptide T
Autoantigens
Antigen-Presenting Cells
Major Histocompatibility Complex
Autoimmune Diseases
Machinery
Personnel
Costs and Cost Analysis
Molecules

Keywords

  • Amino Acid Substitution
  • Cathepsins
  • Cell Line
  • Cell Proliferation
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • Humans
  • Interleukin-2
  • Lysosomes
  • Myelin Basic Protein
  • Peptides
  • T-Lymphocytes
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions. / Burster, Timo; Marin-Esteban, Viviana; Boehm, Bernhard O; Dunn, Shannon; Rotzschke, Olaf; Falk, Kirsten; Weber, Ekkehard; Verhelst, Steven H L; Kalbacher, Hubert; Driessen, Christoph.

In: Biochemical Pharmacology, Vol. 74, No. 10, 15.11.2007, p. 1514-23.

Research output: Contribution to journalArticle

Burster, T, Marin-Esteban, V, Boehm, BO, Dunn, S, Rotzschke, O, Falk, K, Weber, E, Verhelst, SHL, Kalbacher, H & Driessen, C 2007, 'Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions', Biochemical Pharmacology, vol. 74, no. 10, pp. 1514-23. https://doi.org/10.1016/j.bcp.2007.07.037
Burster, Timo ; Marin-Esteban, Viviana ; Boehm, Bernhard O ; Dunn, Shannon ; Rotzschke, Olaf ; Falk, Kirsten ; Weber, Ekkehard ; Verhelst, Steven H L ; Kalbacher, Hubert ; Driessen, Christoph. / Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions. In: Biochemical Pharmacology. 2007 ; Vol. 74, No. 10. pp. 1514-23.
@article{7f371053dc2d4a62bcf75b505f312ca6,
title = "Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions",
abstract = "Multiple Sclerosis (MS) is considered to be a T cell-mediated autoimmune disease. An attractive strategy to prevent activation of autoaggressive T cells in MS, is the use of altered peptide ligands (APL), which bind to major histocompatibility complex class II (MHC II) molecules. To be of clinical use, APL must be capable of resisting hostile environments including the proteolytic machinery of antigen presenting cells (APC). The current design of APL relies on cost- and labour-intensive strategies. To overcome these major drawbacks, we used a deductive approach which involved modifying proteolytic cleavage sites in APL. Cleavage site-directed amino acid substitution of the autoantigen myelin basic protein (MBP) resulted in lysosomal protease-resistant, high-affinity binding peptides. In addition, these peptides mitigated T cell activation in a similar fashion as conventional APL. The strategy outlined allows the development of protease-resistant APL and provides a universal design strategy to improve peptide-based immunotherapeutics.",
keywords = "Amino Acid Substitution, Cathepsins, Cell Line, Cell Proliferation, HLA-DR Antigens, HLA-DRB1 Chains, Humans, Interleukin-2, Lysosomes, Myelin Basic Protein, Peptides, T-Lymphocytes, Journal Article, Research Support, Non-U.S. Gov't",
author = "Timo Burster and Viviana Marin-Esteban and Boehm, {Bernhard O} and Shannon Dunn and Olaf Rotzschke and Kirsten Falk and Ekkehard Weber and Verhelst, {Steven H L} and Hubert Kalbacher and Christoph Driessen",
year = "2007",
month = "11",
day = "15",
doi = "10.1016/j.bcp.2007.07.037",
language = "English",
volume = "74",
pages = "1514--23",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier",
number = "10",

}

TY - JOUR

T1 - Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions

AU - Burster, Timo

AU - Marin-Esteban, Viviana

AU - Boehm, Bernhard O

AU - Dunn, Shannon

AU - Rotzschke, Olaf

AU - Falk, Kirsten

AU - Weber, Ekkehard

AU - Verhelst, Steven H L

AU - Kalbacher, Hubert

AU - Driessen, Christoph

PY - 2007/11/15

Y1 - 2007/11/15

N2 - Multiple Sclerosis (MS) is considered to be a T cell-mediated autoimmune disease. An attractive strategy to prevent activation of autoaggressive T cells in MS, is the use of altered peptide ligands (APL), which bind to major histocompatibility complex class II (MHC II) molecules. To be of clinical use, APL must be capable of resisting hostile environments including the proteolytic machinery of antigen presenting cells (APC). The current design of APL relies on cost- and labour-intensive strategies. To overcome these major drawbacks, we used a deductive approach which involved modifying proteolytic cleavage sites in APL. Cleavage site-directed amino acid substitution of the autoantigen myelin basic protein (MBP) resulted in lysosomal protease-resistant, high-affinity binding peptides. In addition, these peptides mitigated T cell activation in a similar fashion as conventional APL. The strategy outlined allows the development of protease-resistant APL and provides a universal design strategy to improve peptide-based immunotherapeutics.

AB - Multiple Sclerosis (MS) is considered to be a T cell-mediated autoimmune disease. An attractive strategy to prevent activation of autoaggressive T cells in MS, is the use of altered peptide ligands (APL), which bind to major histocompatibility complex class II (MHC II) molecules. To be of clinical use, APL must be capable of resisting hostile environments including the proteolytic machinery of antigen presenting cells (APC). The current design of APL relies on cost- and labour-intensive strategies. To overcome these major drawbacks, we used a deductive approach which involved modifying proteolytic cleavage sites in APL. Cleavage site-directed amino acid substitution of the autoantigen myelin basic protein (MBP) resulted in lysosomal protease-resistant, high-affinity binding peptides. In addition, these peptides mitigated T cell activation in a similar fashion as conventional APL. The strategy outlined allows the development of protease-resistant APL and provides a universal design strategy to improve peptide-based immunotherapeutics.

KW - Amino Acid Substitution

KW - Cathepsins

KW - Cell Line

KW - Cell Proliferation

KW - HLA-DR Antigens

KW - HLA-DRB1 Chains

KW - Humans

KW - Interleukin-2

KW - Lysosomes

KW - Myelin Basic Protein

KW - Peptides

KW - T-Lymphocytes

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.bcp.2007.07.037

DO - 10.1016/j.bcp.2007.07.037

M3 - Article

VL - 74

SP - 1514

EP - 1523

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 10

ER -