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• W2106928984 abstract "Objective The mechanisms underlying bone damage in rheumatoid arthritis (RA) are incompletely understood. We recently identified the shared epitope (SE), an HLA–DRB1–coded 5–amino acid sequence motif carried by the majority of RA patients as a signal transduction ligand that interacts with cell surface calreticulin and accelerates osteoclast (OC)–mediated bone damage in collagen‐induced arthritis (CIA). Given the role of the SE/calreticulin pathway in arthritis‐associated bone damage, we sought to determine the therapeutic targetability of calreticulin. Methods A library of backbone‐cyclized peptidomimetic compounds, all carrying an identical core DKCLA sequence, was synthesized. The ability of these compounds to inhibit SE‐activated signaling and OC differentiation was tested in vitro. The effect on disease severity and OC‐mediated bone damage was studied by weekly intraperitoneal administration of the compounds to DBA/1 mice with CIA. Results Two members of the peptidomimetics library were found to have SE‐antagonistic effects and antiosteoclast differentiation effects at picomolar concentrations in vitro. The lead mimetic compound, designated HS(4‐4)c Trp, potently ameliorated arthritis and bone damage in vivo when administered in picogram doses to mice with CIA. Another mimetic analog, designated HS(3‐4)c Trp, was found to lack activity, both in vitro and in vivo. The differential activity of the 2 analogs depended on minor differences in their respective ring sizes and correlated with distinctive geometry when computationally docked to the SE binding site on calreticulin. Conclusion These findings identify calreticulin as a novel therapeutic target in erosive arthritis and provide sound rationale and early structure/activity relationships for future drug design." @default.
• W2106928984 created "2016-06-24" @default.
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• W2106928984 date "2015-05-01" @default.
• W2106928984 modified "2023-10-16" @default.
• W2106928984 title "Shared Epitope-Antagonistic Ligands: A New Therapeutic Strategy in Mice With Erosive Arthritis" @default.
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• W2106928984 doi "https://doi.org/10.1002/art.39158" @default.
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