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Upregulated cell surface expression of the receptor for advanced glycation end\u2010products (RAGE), a key receptor of innate immune response, is reported in AD. In parallel, RAGE ligands, including A\u03b2 aggregates, HMGB1, and S100B, are elevated in AD brain. Activation of RAGE by these ligands triggers release of inflammatory cytokines and upregulates cell surface RAGE. Despite such observation, there are currently no therapeutics that target RAGE for treatment of AD\u2010associated neuroinflammation. Peptoids, a novel class of potential AD therapeutics, display low toxicity, facile blood\u2010brain barrier permeability, and resistance to proteolytic degradation. In the current study, peptoids were designed to mimic A\u03b2, a ligand that binds the V\u2010domain of RAGE, and curtail RAGE inflammatory activation. We reveal the nanomolar binding capability of peptoids JPT1 and JPT1a to RAGE and demonstrate their ability to attenuate lipopolysaccharide\u2010induced pro\u2010inflammatory cytokine production as well as upregulation of RAGE cell surface expression. These results support RAGE antagonist peptoid\u2010based mimics as a prospective therapeutic strategy to counter neuroinflammation in AD and other neurodegenerative diseases.<\/jats:p>","DOI":"10.1002\/cbic.202300503","type":"journal-article","created":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T22:21:06Z","timestamp":1694125266000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Modulating the RAGE\u2010Induced Inflammatory Response: Peptoids as RAGE Antagonists"],"prefix":"10.1002","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9171-9138","authenticated-orcid":false,"given":"Mihyun Lim","family":"Waugh","sequence":"first","affiliation":[{"name":"Biomedical Engineering Program University of South Carolina  3A46 Swearingen Engineering Center Columbia SC 29208 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren M.","family":"Wolf","sequence":"additional","affiliation":[{"name":"Biomedical Engineering Program University of South Carolina  3A46 Swearingen Engineering Center Columbia SC 29208 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Turner","sequence":"additional","affiliation":[{"name":"Ralph E. Martin Department of Chemical Engineering University of Arkansas  3202 Bell Engineering Center Fayetteville AR 72701 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren N.","family":"Phillips","sequence":"additional","affiliation":[{"name":"Biomedical Engineering Program University of South Carolina  3A46 Swearingen Engineering Center Columbia SC 29208 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon L.","family":"Servoss","sequence":"additional","affiliation":[{"name":"Ralph E. 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