Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease linked to oxidative stress, which is associated with significant morbidity. The NADPH oxidase complex (NOX) produces reactive oxygen species (ROS) that are among the key markers for determining RA’s pathophysiology. Therefore, understanding ROS-regulated molecular pathways and their interaction is necessary for developing novel therapeutic approaches for RA. Here, by combining mouse genetics and biochemistry with clinical tissue analysis, we reveal that in vivo Rubicon interacts with the p22phox subunit of NOX, which is necessary for increased ROS-mediated RA pathogenesis. Furthermore, we developed a series of new aryl propanamide derivatives consisting of tetrahydroindazole and thiadiazole as p22phox inhibitors and selected 2-(tetrahydroindazolyl)phenoxy-N-(thiadiazolyl)propanamide 2 (TIPTP, M.W. 437.44), which showed considerably improved potency, reaching an IC50 value up to 100-fold lower than an inhibitor that we previously synthesized reported N8 peptide-mimetic small molecule (blocking p22phox–Rubicon interaction). Notably, TIPTP treatment showed significant therapeutic effects a mouse model for RA. Furthermore, TIPTP had anti-inflammatory effects ex vivo in monocytes from healthy individuals and synovial fluid cells from RA patients. These findings may have clinical applications for the development of TIPTP as a small molecule inhibitor of the p22phox-Rubicon axis for the treatment of ROS-driven diseases such as RA.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease linked to oxidative stress, which is associated with significant morbidity
We developed a TIPTP (p22 inhibitor) that showed considerably improved potency and selectivity than the previously reported N8 peptide-mimetic small molecule [23 we show that NLRP3 inflammasomes induced by reactive oxygen species (ROS), in vivo, can be inhibited by targeting the p22hox–Rubicon interaction by p22 inhibitor, which showed enhance therapeutic effects ex vivo on monocytes from healthy individuals and synovial fluid cells from RA patients, and in mouse models for RA
collagen antibody-induced arthritis (CAIA) mice were post-treated with TIPTP every 2 days via intraperitoneal injection; notably, CAIA mice transduced with Ad-Rubicon showed median survival of 11 days (20% survival), but equivalent mice treated with TIPTP showed a significant delay in mortality and an increased survival rate (90% survival) (Fig. 5a, bottom)
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease linked to oxidative stress, which is associated with significant morbidity. ROS mediate their effects by activating the signaling pathways of NF-kB and NLRP3 inflammasome These signaling cascades control the synthesis and release of inflammatory cytokines and lead to inflammation of joints and the destruction of macrophages in animals and patients with RA6,20–22. We recently reported an N-terminal eight-amino-acid N8 peptide derived from p22phox and a mimetic compound from in silico virtual screening that interferes with the interaction between Rubicon and p22phox, to strongly suppress the production of ROS and inflammatory cytokines These effects helped to considerably curtail the mortality in mice suffering with polymicrobial sepsis induced by cecal ligation procedure (CLP)[23]. The previously[23] reported the N8 peptidomimetic we described before, which has strong anti-inflammatory and antioxidative effects, proves to be an important resource for the development of a therapeutic against RA
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