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Generation of Induced-pluripotent Stem Cells Using Fibroblast-like Synoviocytes Isolated from Joints of Rheumatoid Arthritis Patients
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Selective Inhibitors of T Cell Receptor Recognition of Antigen-MHC Complexes for Rheumatoid Arthritis
Francesco Ria1,2, Davide Pirolli3, Gabriele Di Sante1,2
1Institute of General Pathology, Università Cattolica del Sacro Cuore, Rome, Italy.
ACS Medicinal Chemistry Letters
|April 19, 2019
Summary
Researchers identified compounds that disrupt T cell receptor interactions with collagen II and MHC class II, offering new rheumatoid arthritis (RA) treatment strategies. This discovery targets key players in RA pathogenesis for drug development.
Area of Science:
- Immunology
- Rheumatology
- Drug Discovery
Background:
- Rheumatoid arthritis (RA) involves autoreactive T cells targeting collagen type II.
- The HLA-DRB1-*04 allele is implicated in RA development.
- T cell receptor (TCR) and collagen II-MHC class II interactions are critical in RA.
Purpose of the Study:
- To develop a structure-based pharmacophore model for small molecule inhibitors.
- To identify compounds that interfere with TCR/collagenII-MHCII interactions.
- To explore new therapeutic targets for rheumatoid arthritis.
Main Methods:
- Developed a pharmacophore model from protein-protein interface structures.
- Performed virtual screening using the 3D model.
- Conducted experimental validation of identified compounds.
Main Results:
- Identified three compounds that inhibit TCR/collagenII-MHCII interactions.
- Achieved inhibition constants (Ki) below 10 μM for the identified compounds.
- Validated the potential of these compounds as RA therapeutics.
Conclusions:
- Protein-protein interactions between TCR and collagen II-MHC II are viable drug targets for RA.
- Small molecule inhibitors targeting these interactions show promise for RA treatment.
- This study opens new avenues for developing RA therapies.
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