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
  • 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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