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Selective alpha4beta7 integrin antagonists and their potential as antiinflammatory agents
Nathan J P Dubree1, Dean R Artis, Georgette Castanedo
1Department of Bioorganic Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Journal of Medicinal Chemistry
|July 26, 2002
Summary
Researchers discovered potent peptide antagonists targeting alpha4beta7 integrins, crucial for lymphocyte trafficking in autoimmune diseases. These selective inhibitors show promise for treating gastrointestinal inflammatory conditions like Crohn's disease.
Area of Science:
- Immunology
- Molecular Biology
- Drug Discovery
Background:
- Leukocyte accumulation drives autoimmune diseases.
- Integrin alpha4beta7 and MAdCAM mediate lymphocyte homing to the GI tract.
- Targeting alpha4beta7-MAdCAM interaction offers potential for GI-specific anti-inflammatory therapy.
Purpose of the Study:
- To discover and optimize potent and selective alpha4beta7 integrin antagonists.
- To evaluate the efficacy of these antagonists in inhibiting lymphocyte homing and MAdCAM binding.
Main Methods:
- Peptide-phage display library screening for alpha4beta7 antagonists.
- In vitro assays to assess competitive binding to MAdCAM.
- In vivo studies in murine models to evaluate lymphocyte homing inhibition.
- Structure-activity relationship studies through chemical modification.
Main Results:
- Identification of highly potent and selective alpha4beta7 antagonists from a peptide library.
- Optimization yielded heptapeptide inhibitors that block MAdCAM binding and lymphocyte homing.
- Demonstrated over 500-fold selectivity shift for alpha4beta7 over alpha4beta1 by modifying a single carboxylate moiety.
- These represent the first peptides with demonstrated potency and selectivity for alpha4beta7 against other integrins.
Conclusions:
- Peptide-based alpha4beta7 antagonists are effective in blocking lymphocyte trafficking to the GI tract.
- These antagonists hold significant potential as targeted anti-inflammatory agents for autoimmune diseases.
- The study highlights the development of novel, highly selective integrin antagonists.