{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:25:57Z","timestamp":1785432357998,"version":"3.56.0"},"reference-count":139,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018990","name":"Alfaisal University","doi-asserted-by":"publisher","award":["IRG25444"],"award-info":[{"award-number":["IRG25444"]}],"id":[{"id":"10.13039\/501100018990","id-type":"DOI","asserted-by":"publisher"}]},{"award":["IRG25444"],"award-info":[{"award-number":["IRG25444"]}],"id":[{"id":"https:\/\/ror.org\/00cdrtq48","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Amyloid-\u03b2 (A\u03b2) protein, a cleavage product of the amyloid precursor protein (APP), is the main component of neuritic plaques in Alzheimer\u2019s disease (AD), and its accumulation has been considered as the molecular driver of Alzheimer\u2019s pathogenesis. A\u03b2 has been a primary target for therapy since the amyloid cascade theory was put forth, with methods designed to prevent the generation of A\u03b2. The APP 5\u2032-untranslated region (UTR) mRNA encodes a functional structured iron-responsive element (IRE) that represents a potential target for small molecule inhibitors as an anti-amyloid therapy for AD. Here, we offer a comprehensive strategy that uses RNA-targeted binding to inhibit APP translation. The IRE family is among the few 3-D mRNA regulatory elements with a known 3-D structure. Accordingly, we exploit these structural and functional characteristics as our strategy to target APP IRE structured mRNA to identify anti-amyloid drugs. The mRNA encoding proteins involved in iron metabolism are regulated by this family of similar nucleotide sequences. Post-transcriptional control of cytoplasmic mRNA is a rapidly developing area of biomedicine. Across animals, evolutionarily conserved IRE mRNAs serve as a model system for 3-D mRNAs. IRE mRNAs have shown great promise for chemical manipulation of mRNA and protein expression in biological systems by yielding \u201cproof of principle\u201d data for small molecules targeting mRNA structures. A novel approach to identifying RNA-directed therapeutics to regulate APP expression and A\u03b2-peptide generation for AD treatments is exemplified by APP 5\u2032-UTR-directed small molecule inhibitors.<\/jats:p>","DOI":"10.3390\/ijms27093978","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T15:01:18Z","timestamp":1777474878000},"page":"3978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Small-Molecule Targeting of the Iron-Responsive Element in the APP mRNA 5\u2032-UTR to Control Amyloid Translation in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2300-4595","authenticated-orcid":false,"given":"Mateen A.","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Life Science, College of Science and General Studies, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3575-6460","authenticated-orcid":false,"given":"Hassan S.","family":"Shaibah","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/nrn.2017.29","article-title":"Not just amyloid: Physiological functions of the amyloid precursor protein family","volume":"18","author":"Deller","year":"2017","journal-title":"Nat. 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