Organocatalytic Switches of DNA Glycosylase OGG1 Catalyze a Highly Efficient AP‐Lyase Function

8-oxoGuanine DNA glycosylase 1 (OGG1) is the first known target of organocatalytic switches (ORCAs), which rewrite the biochemical function of the enzyme through redirection of its preferred substrate from 8-oxoG to AP sites. Previously, different ORCA chemotypes were shown to enhance the operational pH window for OGG1, possibly through direct involvement in proton transfer events during DNA strand cleavage. Accordingly, compound pK<sub>a</sub> is a crucial and necessary consideration for the identification and application of future OGG1 ORCAs. Here, we identify a minimal structure of organocatalytic switches-4-anilino pyridines and 6-anilino pyrimidines-which are dimethyl-amino-pyridine (DMAP)-type Brønsted bases binding the active site of OGG1. Systematic interrogation of compound basicity through modulation of electron-withdrawing (EWG) and electron-donating (EDG) substituents reveals that a pK<sub>a</sub> less or equal to the assay pH is a viable parameter for prediction of compound activity. The lead structure (AC<sub>50</sub> 13 nM, pK<sub>a</sub> 7.0) was then identified as a potent scaffold from a screen in a patient-derived 3D model of metabolic dysfunction-associated steatohepatitis (MASH), where it reduced hepatic fibrosis by 35%. Collectively, these findings deepen the knowledge of this novel modulator class, with important implications for future enzyme targets and probe development.

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Publication Details

Journal
Chemistry - A European Journal
Published
2025-04-28
DOI
https://doi.org/10.1002/chem.202500382
Citations
8
Primary Topic
DNA and Nucleic Acid Chemistry
Type
article
Field-Weighted Citation Impact
6.45

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article

Organocatalytic Switches of DNA Glycosylase OGG1 Catalyze a Highly Efficient AP‐Lyase Function

Kang‐Cheng Liu, Evert J. Homan, Femke M. Hormann, Alicia del Prado et al.
8 citations
Chemistry - A European Journal
DNA and Nucleic Acid Chemistry
6.45
article

Organocatalytic Switches of DNA Glycosylase OGG1 Catalyze a Highly Efficient AP‐Lyase Function

Kang‐Cheng Liu, Evert J. Homan, Femke M. Hormann, Alicia del Prado, Kaixin Zhou, Miguel de Vega, Marek Varga, Thomas Helleday, Pål Stenmark, Sean G. Rudd, Jonathan Haslam, Volker Martin Lauschke, Nicholas D. D’Arcy-Evans, Olov A. Wallner, O. Gileadi, Aurino M. Kemas, Maurice Michel, Yi Zhong, Ingrid Almlöf, Elisée Wiita, Florian Ortis, Oryn Purewal-Sidhu, Mario Kehler, Heather Gildie, Karolina Singerova, Zuzanna Szaruga, Emma Scaletti Hutchinson, Elinor Hesslefors Nairn, Yvonne Plattner
article en
8 citations

Abstract

8-oxoGuanine DNA glycosylase 1 (OGG1) is the first known target of organocatalytic switches (ORCAs), which rewrite the biochemical function of the enzyme through redirection of its preferred substrate from 8-oxoG to AP sites. Previously, different ORCA chemotypes were shown to enhance the operational pH window for OGG1, possibly through direct involvement in proton transfer events during DNA strand cleavage. Accordingly, compound pK<sub>a</sub> is a crucial and necessary consideration for the identification and application of future OGG1 ORCAs. Here, we identify a minimal structure of organocatalytic switches-4-anilino pyridines and 6-anilino pyrimidines-which are dimethyl-amino-pyridine (DMAP)-type Brønsted bases binding the active site of OGG1. Systematic interrogation of compound basicity through modulation of electron-withdrawing (EWG) and electron-donating (EDG) substituents reveals that a pK<sub>a</sub> less or equal to the assay pH is a viable parameter for prediction of compound activity. The lead structure (AC<sub>50</sub> 13 nM, pK<sub>a</sub> 7.0) was then identified as a potent scaffold from a screen in a patient-derived 3D model of metabolic dysfunction-associated steatohepatitis (MASH), where it reduced hepatic fibrosis by 35%. Collectively, these findings deepen the knowledge of this novel modulator class, with important implications for future enzyme targets and probe development.

Chemistry - A European JournalVol. 31(33)
Karolinska University Hospital (SE), Central South University (CN), Stockholm University (SE), University of St Andrews (GB), Science for Life Laboratory (SE), Structural Genomics Consortium (CA), Karolinska Institutet (SE), Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE), Centro de Biología Molecular Severo Ochoa (ES), Second Xiangya Hospital of Central South University (CN), Universidad Autónoma de Madrid (ES), University of Tübingen (DE), University of Sheffield (GB)
Åke Wiberg Stiftelse, McGill University, Diamond Light Source, European Federation of Pharmaceutical Industries and Associations, European Commission, Cancerfonden, Karolinska Institutet, Novo Nordisk, Kungliga Tekniska Högskolan, Vetenskapsrådet, Stockholms Universitet, Novo Nordisk Fonden, Agencia Estatal de Investigación
Openalex Percentile: Top 3%
DNA and Nucleic Acid Chemistry
6.45
DOIOpen Access PDFOpenAlex
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