Giving an Enzyme Scissors: Serotonin Derivatives as Potent Organocatalytic Switches for DNA Repair Enzyme OGG1
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.
Authors
- Allan J. B. Watson (ORCID: https://orcid.org/0000-0002-1582-4286)
- Stella Karsten (ORCID: https://orcid.org/0000-0001-6191-4314)
- Evert J. Homan (ORCID: https://orcid.org/0000-0002-9057-1848)
- Alicia del Prado (ORCID: https://orcid.org/0000-0002-5480-0367)
- Kaixin Zhou (ORCID: https://orcid.org/0000-0002-4751-7248)
- Miguel de Vega (ORCID: https://orcid.org/0000-0003-1285-7549)
- Kirill Mamonov (ORCID: https://orcid.org/0000-0001-5971-4305)
- Marek Varga (ORCID: https://orcid.org/0000-0002-9685-8145)
- Emily C. Hank (ORCID: https://orcid.org/0000-0002-3777-4697)
- Thomas Helleday (ORCID: https://orcid.org/0000-0002-7384-092X)
- Pål Stenmark (ORCID: https://orcid.org/0000-0003-4777-3417)
- Kirsty Bentley
- Emma Rose Scaletti (ORCID: https://orcid.org/0000-0002-8741-8981)
- Olov A. Wallner (ORCID: https://orcid.org/0000-0002-6481-237X)
- Alice Eddershaw (ORCID: https://orcid.org/0000-0002-8381-4135)
- Maurice Michel (ORCID: https://orcid.org/0000-0003-3261-2493)
- Sabbir Ahmed (ORCID: https://orcid.org/0000-0001-8496-8745)
- Martin Scobie (ORCID: https://orcid.org/0000-0002-7073-8495)
- Mario Prejanò (ORCID: https://orcid.org/0000-0002-9140-6246)
- Ingrid Almlöf
- Elisée Wiita
- Florian Ortis (ORCID: https://orcid.org/0000-0002-0458-5187)
- Natálie Rudolfová (ORCID: https://orcid.org/0009-0000-6725-2198)
- Alessia Dodaro
Institutions
- Karolinska University Hospital (SE)
- Stockholm University (SE)
- University of St Andrews (GB)
- Science for Life Laboratory (SE)
- Karolinska Institutet (SE)
- Industriale Chimica (Italy) (IT)
- Università degli Studi Internazionali di Roma (IT)
- Centro de Biología Molecular Severo Ochoa (ES)
- Institute of Molecular Biology and Biophysics (RU)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-10-15
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01454
- Citations
- 1
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.81