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

doi:10.1021/acsmedchemlett.8b00601

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

ACS Med Chem Lett. 2019 Mar 13;10(4):644-649. doi: 10.1021/acsmedchemlett.8b00601. eCollection 2019 Apr 11.

Authors

Francesco Ria^{1

2}, Davide Pirolli³, Gabriele Di Sante^{1

2}, Benedetta Righino⁴, Elisa Gremese^{5

6}, Jacopo Gervasoni^{7

4}, Chiara Nicolò¹, Bruno Giardina⁴, Gianfranco Ferraccioli^{5

6}, Maria Cristina De Rosa³

Affiliations

¹ Institute of General Pathology, Università Cattolica del Sacro Cuore, Rome, Italy.
² Institute of General Pathology, Fondazione Policlinico Universitario "A. Gemelli" - I.R.C.C.S., Rome, Italy.
³ Institute of Chemistry of Molecular Recognition (ICRM) - CNR, Rome, Italy.
⁴ Institute of Biochemistry and Clinical Biochemistry, Università Cattolica del Sacro Cuore, Rome, Italy.
⁵ Institute of Rheumatology, Università Cattolica del Sacro Cuore, Rome, Italy.
⁶ Division of Rheumatology, Fondazione Policlinico Universitario "A. Gemelli" - I.R.C.C.S., Rome, Italy.
⁷ U.O.C. Biochimica Clinica, Fondazione Policlinico Universitario "A. Gemelli" - I.R.C.C.S., Rome, Italy.

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 (K _i values below 10 μM) and open up new possibilities in the treatment of RA.