{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T16:07:14Z","timestamp":1782835634938,"version":"3.54.5"},"reference-count":34,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2025,12,11]]},"abstract":"<jats:p>\n                    Adenosine deaminases acting on RNA (ADAR) catalyze the deamination of adenosine to inosine in double\u2010stranded RNA. Because inosine is read as guanosine during translation, this process enables programmable A\u2010to\u2010G recoding at the transcript level. ADARs can be harnessed for therapeutic correction of pathogenic mutations through site\u2010directed RNA editing with guide RNAs. To expand the design space of editing\u2010enabling guides, we applied EMERGe, a high\u2010throughput screening platform, to identify motifs targeting a premature termination codon in the\n                    <jats:italic>MeCP2<\/jats:italic>\n                    transcript associated with Rett syndrome. This uncovered a guide RNA motif that supported efficient ADAR2\u2010mediated editing\n                    <jats:italic>in\u2009vitro<\/jats:italic>\n                    , featuring a 5\u2032\u2010GUG\u20103' sequence predicted to form an asymmetric loop. To enable therapeutic application, structure\u2013activity relationship studies and chemical optimization were performed, yielding a fully modified guide RNA with 2\u2032\u2010O\u2010methyl, 2\u2032\u2010fluoro, and phosphorothioate linkages. This stabilized guide retained the activity of unmodified RNA and showed enhanced nuclease resistance. The optimized guide induces dose\u2010dependent editing at two MECP2 loci in reporter assays in HEK293T cells, demonstrating that EMERGe\u2010selected motifs can be rendered viable in cells through targeted chemical modification. These findings highlight the utility of EMERGe as a discovery platform and establish a pipeline for identifying and optimizing editing\u2010enabling guide RNA features beyond traditional design rules.\n                  <\/jats:p>","DOI":"10.1002\/cbic.202500735","type":"journal-article","created":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T05:40:07Z","timestamp":1763790007000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Discovery and Tuning of RNA Editing Guides via High\u2010Throughput Screening and Chemical Modification"],"prefix":"10.1002","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4536-584X","authenticated-orcid":false,"given":"Prince J.","family":"Salvador","sequence":"first","affiliation":[{"name":"Department of Chemistry University of California, Davis  Davis California 95616 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