{"doi":"10.3389/fchem.2020.601477","title":"Characterization and Validation of Arg286 Residue of IL-1RAcP as a Potential Drug Target for Osteoarthritis","abstract":"Osteoarthritis (OA) is the most common form of arthritis and the fastest growing cause of chronic disability in the world. Formation of the ternary IL-1β /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-1β 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-1β 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 IC 50 value of 304 pM in a pull-down model of complex formation, and reduced IL-1β signaling in a cell model by 90% at 2 μM. 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.","journal":"Frontiers in Chemistry","year":2021,"id":202100,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9597,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":782159,"name":"Kelsey Mitchell","orcid":null,"position":1,"is_corresponding":false},{"id":424764,"name":"Ngoc Vuong","orcid":"0000-0002-2199-2569","position":2,"is_corresponding":false},{"id":781607,"name":"Kyung Hyeon Lee","orcid":"0000-0002-6794-5223","position":3,"is_corresponding":false},{"id":782160,"name":"Reva Joshi","orcid":null,"position":4,"is_corresponding":false},{"id":242176,"name":"Virginia Espina","orcid":"0000-0001-5080-5972","position":5,"is_corresponding":false},{"id":782161,"name":"Amanda Haymond Still","orcid":null,"position":6,"is_corresponding":false},{"id":781608,"name":"Carter J. Gottschalk","orcid":"0000-0002-8021-4556","position":7,"is_corresponding":false},{"id":411278,"name":"Anne M. Brown","orcid":"0000-0001-6951-8228","position":8,"is_corresponding":false},{"id":648224,"name":"Mikell Paige","orcid":"0000-0001-9292-1277","position":9,"is_corresponding":false},{"id":242177,"name":"Lance A. Liotta","orcid":"0000-0001-5155-7907","position":10,"is_corresponding":false},{"id":424770,"name":"Alessandra Luchini","orcid":"0000-0003-1599-0214","position":11,"is_corresponding":false},{"id":782158,"name":"Angela Dailing","orcid":null,"position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-18T23:51:05.955461Z","pmid":"33614593","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}