2. Academic Validation
  3. Giving an Enzyme Scissors: Serotonin Derivatives as Potent Organocatalytic Switches for DNA Repair Enzyme OGG1

Giving an Enzyme Scissors: Serotonin Derivatives as Potent Organocatalytic Switches for DNA Repair Enzyme OGG1

  • J Med Chem. 2025 Nov 13;68(21):22455-22483. doi: 10.1021/acs.jmedchem.5c01454.
Marek Varga 1,  Florian Ortis 2,  Alicia Del Prado 3,  Alice Eddershaw 4,  Emma Scaletti Hutchinson 5,  Emily C Hank 2,  Kaixin Zhou 2,  Natálie Rudolfová 4,  Alessia Dodaro 6,  Elisée Wiita 2,  Ingrid Almlöf 2,  Stella Karsten 2,  Kirill Mamonov 2,  Sara H Ahmed 1,  Kirsty Bentley 2,  Olov Wallner 2,  Evert J Homan 2,  Martin Scobie 2,  Thomas Helleday 2,  Mario Prejanò 6,  Pål Stenmark 5,  Miguel de Vega 3,  Allan J B Watson 1,  Maurice Michel 2 4
Affiliations

Affiliations

  • 1 EaStCHEM, School of Chemistry, University of St Andrews, St Andrews KY16 9ST, United Kingdom.
  • 2 Karolinska Institute, Oncology and Pathology Science for Life Laboratory, Stockholm 171 65, Sweden.
  • 3 Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid 28049, Spain.
  • 4 Karolinska Institute, Oncology and Pathology, Center for Molecular Medicine, Karolinska Institute and Karolinska Hospital, L8:05, Visionsgatan 18, Stockholm 171 76, Sweden.
  • 5 Stockholm University, Biochemistry and Biophysics, Stockholm 106 91, Sweden.
  • 6 Dipartimento di Chimica E Tecnologie Chimiche, Università Degli Studi della, Rende, Calabria 87036, Italy.
PMID: 41092057 DOI: 10.1021/acs.jmedchem.5c01454
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 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.

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