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Chemogenomics with peptide secondary structure mimetics
Masakatsu Eguchi1, Michael McMillan, Cu Nguyen
1Pacific Northwest Research Institute, Seattle, Washington 98122, USA.
Combinatorial Chemistry & High Throughput Screening
|December 20, 2003
Summary
Researchers developed small molecule inhibitors targeting oxidoreductases, crucial in inflammatory diseases like asthma. This study validates thioredoxin as a therapeutic target using a novel chemogenomic approach in a mouse asthma model.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Redox regulation of transcription factors, including activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappaB), plays a significant role in inflammatory diseases.
- Human thioredoxin (TRX), an oxidoreductase, was initially identified for its role in augmenting interleukin-2 receptor alpha (IL-2R alpha) production in HTLV-1 infected T-cells.
Purpose of the Study:
- To develop small molecule inhibitors targeting oxidoreductase molecular targets.
- To validate the therapeutic potential of targeting thioredoxin in a murine asthma model.
Main Methods:
- Utilized a chemogenomic approach employing an extended strand templated library.
- Employed solid-phase synthesis for rapid generation of peptide secondary structure mimetics.
- Validated small molecule inhibitors in a murine asthma model.
Main Results:
- Successfully developed small molecule inhibitors targeting oxidoreductase activity.
- Demonstrated the potential of these inhibitors in a relevant disease model.
Conclusions:
- The study validates oxidoreductases, specifically thioredoxin, as druggable targets for inflammatory diseases.
- The developed chemogenomic approach offers a promising strategy for identifying pharmaceutical leads based on protein-peptide interactions.