Dailing, AngelaMitchell, KelseyNgoc VuongLee, Kyung HyeonJoshi, RevaEspina, VirginiaStill, Amanda HaymondGottschalk, Carter J.Brown, Anne M.Paige, MikellLiotta, Lance A.Luchini, Alessandra2021-05-212021-05-212021-02-032296-2646601477http://hdl.handle.net/10919/103431Osteoarthritis (OA) is the most common form of arthritis and the fastest growing cause of chronic disability in the world. Formation of the ternary IL-1 beta /IL-1R1/IL-1RAcP protein complex and its downstream signaling has been implicated in osteoarthritis pathology. Current OA therapeutic approaches target either the cytokine IL-1 beta or the primary receptor IL-1RI but do not exploit the potential of the secondary receptor IL-1RAcP. Our previous work implicated the Arg286 residue of IL-1RAcP as a key mediator of complex formation. Molecular modeling confirmed Arg286 as a high-energy mediator of the ternary IL-1 beta complex architecture and interaction network. Anti-IL-1RAcP monoclonal antibodies (mAb) targeting the Arg286 residue were created and were shown to effectively reduce the influx of inflammatory cells to damaged joints in a mouse model of osteoarthritis. Inhibitory peptides based on the native sequence of IL-1RAcP were prepared and examined for efficacy at disrupting the complex formation. The most potent peptide inhibitor had an IC50 value of 304 pM in a pull-down model of complex formation, and reduced IL-1 beta signaling in a cell model by 90% at 2 mu M. Overall, therapies that target the Arg286 region surface of IL-1RAcP, and disrupt subsequent interactions with subunits, have the potential to serve as next generation treatments for osteoarthritis.application/pdfenCreative Commons Attribution 4.0 Internationalmolecular dynamicsmolecular modelingprotein paintingpeptidetargeted inhibitorsArticle - Refereedhttps://doi.org/10.3389/fchem.2020.601477833614593