Characterization and Validation of Arg286 Residue of IL-1RAcP as a Potential Drug Target for Osteoarthritis

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dc.contributor.authorDailing, Angelaen
dc.contributor.authorMitchell, Kelseyen
dc.contributor.authorNgoc Vuongen
dc.contributor.authorLee, Kyung Hyeonen
dc.contributor.authorJoshi, Revaen
dc.contributor.authorEspina, Virginiaen
dc.contributor.authorStill, Amanda Haymonden
dc.contributor.authorGottschalk, Carter J.en
dc.contributor.authorBrown, Anne M.en
dc.contributor.authorPaige, Mikellen
dc.contributor.authorLiotta, Lance A.en
dc.contributor.authorLuchini, Alessandraen
dc.contributor.departmentBiochemistryen
dc.contributor.departmentUniversity Librariesen
dc.date.accessioned2021-05-21T15:00:53Zen
dc.date.available2021-05-21T15:00:53Zen
dc.date.issued2021-02-03en
dc.description.abstractOsteoarthritis (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.en
dc.description.notesThis work was supported by the National Institutes of Health (grants 1R21CA177535, 1R33CA173359, 1R01AR068436, and 1R33CA206937), by the Virginia Center for Health Innovation, and by the Virginia Center for Innovative Technology, Commonwealth Research Commercialization Fund. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.en
dc.description.sponsorshipNational Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1R21CA177535, 1R33CA173359, 1R01AR068436, 1R33CA206937]; Virginia Center for Health Innovation; Virginia Center for Innovative Technology, Commonwealth Research Commercialization Funden
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fchem.2020.601477en
dc.identifier.issn2296-2646en
dc.identifier.other601477en
dc.identifier.pmid33614593en
dc.identifier.urihttp://hdl.handle.net/10919/103431en
dc.identifier.volume8en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectmolecular dynamicsen
dc.subjectmolecular modelingen
dc.subjectprotein paintingen
dc.subjectpeptideen
dc.subjecttargeted inhibitorsen
dc.titleCharacterization and Validation of Arg286 Residue of IL-1RAcP as a Potential Drug Target for Osteoarthritisen
dc.title.serialFrontiers in Chemistryen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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