Selective Inhibitors of T Cell Receptor Recognition of Antigen-MHC Complexes for Rheumatoid Arthritis

Francesco Ria, Davide Pirolli, Gabriele Di Sante, Benedetta Righino, Elisa Gremese, Jacopo Gervasoni, Chiara Nicolò, Bruno Giardina, Gianfranco Ferraccioli, Maria Cristina De Rosa

Research output: Contribution to journalArticle

Abstract

Autoreactive T cells specific to human collagen type II have a crucial role in the development of rheumatoid arthritis (RA) in the context of MHC class II allele HLA-DRB1-*04. The protein-protein interactions between the T cell receptor (TCR) and the type II collagen bound to the allele MHC of class II may thus represent the target for the development of new drugs against RA. In this study, a structure-based pharmacophore model for potential small molecule inhibitors was developed from protein-protein interface structure. The 3D model obtained was used for a virtual screening workflow, which resulted in three hits for experimental follow up. Three compounds have been identified that interfere with the TCR/collagenII-MHCII (Ki values below 10 μM) and open up new possibilities in the treatment of RA.

Original languageEnglish
Pages (from-to)644-649
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume10
Issue number4
DOIs
Publication statusPublished - Apr 11 2019

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Ria, F., Pirolli, D., Di Sante, G., Righino, B., Gremese, E., Gervasoni, J., Nicolò, C., Giardina, B., Ferraccioli, G., & De Rosa, M. C. (2019). Selective Inhibitors of T Cell Receptor Recognition of Antigen-MHC Complexes for Rheumatoid Arthritis. ACS Medicinal Chemistry Letters, 10(4), 644-649. https://doi.org/10.1021/acsmedchemlett.8b00601