Targeting protein-protein interaction for immunomodulation: A sunflower trypsin inhibitor analog peptidomimetic suppresses RA progression in CIA model

Protein-protein interactions (PPI) of co-stimulatory molecules CD2-CD58 are important in the early stage of an immune response, and increased expression of these co-stimulatory molecules is observed in the synovial region of joints in rheumatoid arthritis (RA) patients. A CD2 epitope region that binds to CD58 was grafted on to sunflower trypsin inhibitor (SFTI) template structure to inhibit CD2-CD58 PPI. The peptide was incorporated with an organic moiety dibenzofuran (DBF) in its structure. The designed peptidomimetic was studied for its ability to inhibit CD2-CD58 interactions in vitro, and its thermal and enzymatic stability was evaluated. Stability studies indicated that the grafted peptidomimetic was stable against trypsin cleavage. In vivo studies using the collagen-induced arthritis (CIA) model in mice indicated that the peptidomimetic was able to slow down the progress of arthritis, an autoimmune disease in the mice model. These studies suggest that with the grafting of organic functional groups in the stable peptide template SFTI stabilizes the peptide structure, and these peptides can be used as a template to design stable peptides for therapeutic purposes. ?? 2022 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Automated summary

Protein-protein interactions (PPI) of co-stimulatory molecules CD2-CD58 play an important role in the early stage of the immune response. Increased expression of these co-stimulatory molecules has been observed in the synovial region of joints in rheumatoid arthritis (RA) patients. In this study, a peptidomimetic was designed to inhibit CD2-CD58 PPI by grafting a CD2 epitope region onto a sunflower trypsin inhibitor (SFTI) template structure. The peptidomimetic showed stability against trypsin cleavage and was able to slow down the progress of arthritis in a murine model. These findings suggest that functional group grafting in stable peptide templates can be used to design stable peptides for therapeutic purposes.