Investigation of a squaramide motif as a bioisostere of the amino-acid group of S-adenosyl-L-methionine and its functional impact on RNA methylation
Methyltransferases (MTases) are enzymes that methylate biomolecules like proteins, DNA, RNA, lipids, and small molecules, mostly using S-adenosyl-L-methionine (SAM) as a methyl donor. MTases have emerged as promising drug targets, and SAM analogues are widely employed to investigate their involvement in diseases and to develop effective drug therapies. We designed and synthesized stable SAM analogues with a squaramide moiety mimicking the methionine side chain. These compounds were tested on the two human m⁶A RNA MTases METTL3/14 and METTL16. While these SAM analogues failed to support catalytic activity, they exhibited potent inhibitory effects on the METTL3/14 activity. Surprisingly, some of these compounds demonstrated remarkable potency (K<sub>I</sub> = 3 nM) and specificity, likely attributed to the unique properties of the squaramide motif. Docking studies showed they bind METTL3/14 cofactor pocket similarly to SAM, allowing us to make new hypothesis on the catalytic mechanism. Our synthetic method expands the structural diversity of SAM analogues, providing a foundation for developing selective RNA MTase inhibitors.
Authors
- Vladimir I. Martynov (ORCID: https://orcid.org/0000-0003-4923-6842)
- Luc Ponchon (ORCID: https://orcid.org/0000-0002-4094-4853)
- Jiajin Du (ORCID: https://orcid.org/0000-0002-3409-8072)
- Mélanie Ethève‐Quelquejeu (ORCID: https://orcid.org/0000-0002-4105-3243)
- Elisa Frezza (ORCID: https://orcid.org/0000-0003-0122-7859)
- Christelle Vasnier (ORCID: https://orcid.org/0000-0003-3265-2997)
- Emmanuelle Braud (ORCID: https://orcid.org/0000-0002-2563-2675)
- Bruno Sargueil (ORCID: https://orcid.org/0000-0003-4483-355X)
- Frédéric Bonhomme (ORCID: https://orcid.org/0000-0001-6797-289X)
- Dylan Coelho
- Batoul Mahcene
Institutions
- Centre National de la Recherche Scientifique (FR)
- Institut Pasteur (FR)
- Institut Universitaire de France (FR)
- Université Paris Cité (FR)
- Sorbonne Paris Cité (FR)
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (FR)
- Epigénétique et Destin Cellulaire (FR)
Publication Details
- Journal
- Communications Chemistry
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1038/s42004-025-01627-7
- Citations
- 4
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Sidaction
- Agence Nationale de la Recherche
- Ministère de l'Enseignement Supérieur, de la Recherche, de la Science et de la Technologie
- China Scholarship Council
- Centre National de la Recherche Scientifique
- Institut Universitaire de France
- Chinese Government Scholarship