{"entity": "publication", "iuid": "172755f770e243579d9d401b29efec67", "timestamp": "2026-08-20T20:45:55.927Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/172755f770e243579d9d401b29efec67.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/172755f770e243579d9d401b29efec67"}}, "title": "Giving an Enzyme Scissors: Serotonin Derivatives as Potent Organocatalytic Switches for DNA Repair Enzyme OGG1.", "authors": [{"family": "Varga", "given": "Marek", "initials": "M", "orcid": "0000-0002-9685-8145", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/707532fc225c49d1b2d4f9bec632e13f.json"}}, {"family": "Ortis", "given": "Florian", "initials": "F"}, {"family": "Del Prado", "given": "Alicia", "initials": "A", "orcid": "0000-0002-5480-0367", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7625321e94ab4cb5ba256de247cd0fcd.json"}}, {"family": "Eddershaw", "given": "Alice", "initials": "A", "orcid": "0000-0002-8381-4135", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/bef07e3914ad492d99119e687845f3c4.json"}}, {"family": "Scaletti Hutchinson", "given": "Emma", "initials": "E", "orcid": "0000-0002-8741-8981", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/77be7f5d51564a75a753579e976c7c72.json"}}, {"family": "Hank", "given": "Emily C", "initials": "EC", "orcid": "0000-0002-3777-4697", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/2b412977f2364bef9ec63aa5e552331a.json"}}, {"family": "Zhou", "given": "Kaixin", "initials": "K"}, {"family": "Rudolfov\u00e1", "given": "Nat\u00e1lie", "initials": "N"}, {"family": "Dodaro", "given": "Alessia", "initials": "A"}, {"family": "Wiita", "given": "Elis\u00e9e", "initials": "E"}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Karsten", "given": "Stella", "initials": "S"}, {"family": "Mamonov", "given": "Kirill", "initials": "K"}, {"family": "Ahmed", "given": "Sara H", "initials": "SH"}, {"family": "Bentley", "given": "Kirsty", "initials": "K"}, {"family": "Wallner", "given": "Olov", "initials": "O"}, {"family": "Homan", "given": "Evert J", "initials": "EJ"}, {"family": "Scobie", "given": "Martin", "initials": "M"}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Prejan\u00f2", "given": "Mario", "initials": "M", "orcid": "0000-0002-9140-6246", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3149d1c394e5447b873012134ed902ac.json"}}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9791bc0d7463417899d6953b5ca1bac3.json"}}, {"family": "de Vega", "given": "Miguel", "initials": "M", "orcid": "0000-0003-1285-7549", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6196fa790b4645c3acef45a87cdac3d0.json"}}, {"family": "Watson", "given": "Allan J B", "initials": "AJB", "orcid": "0000-0002-1582-4286", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/991264ae319e4e95a51e0b47b995c66e.json"}}, {"family": "Michel", "given": "Maurice", "initials": "M"}], "type": "journal article", "published": "2025-11-13", "journal": {"title": "J Med Chem", "issn": "1520-4804", "volume": "68", "issue": "21", "pages": "22455-22483", "issn-l": "0022-2623"}, "abstract": "The base excision repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG1) plays a central role in maintaining genome integrity and mediating cellular responses to oxidative stress. As such, it represents an attractive target for pharmaceutical modulation. Small-molecule organocatalytic switches (ORCAs) greatly enhance the rate of OGG1-catalyzed cleavage of DNA abasic sites, thereby accelerating DNA repair. Here, we present the discovery and hit-to-lead optimization of a novel class of highly potent serotonin-derived ORCAs with greatly improved pharmacokinetic properties. Biochemical assays, X-ray crystallography, and molecular dynamics simulations point toward a water-mediated mechanism of activation, distinct from previously proposed Br\u00f8nsted base-assisted models. These findings establish serotonin-based ORCAs as promising chemical probes and potential leads for therapeutic modulation of OGG1 in oxidative stress-driven diseases.", "doi": "10.1021/acs.jmedchem.5c01454", "pmid": "41092057", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC12621200"}], "notes": [], "created": "2026-08-20T08:10:54.321Z", "modified": "2026-08-20T08:10:54.746Z"}