Giving an Enzyme Scissors: Serotonin Derivatives as Potent Organocatalytic Switches for DNA Repair Enzyme OGG1.
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Varga M, Ortis F, Del Prado A, Eddershaw A, Scaletti Hutchinson E, Hank EC, Zhou K, Rudolfová N, Dodaro A, Wiita E, Almlöf I, Karsten S, Mamonov K, Ahmed SH, Bentley K, Wallner O, Homan EJ, Scobie M, Helleday T, Prejanò M, Stenmark P, de Vega M, Watson AJB, Michel M
J Med Chem 68 (21) 22455-22483 [2025-11-13; online 2025-10-15]
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 Brønsted 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.
PubMed 41092057
DOI 10.1021/acs.jmedchem.5c01454
Crossref 10.1021/acs.jmedchem.5c01454