Du Jianxun, Mahcene Batoul, Martynov Valerii, Frezza Elisa, Vasnier Christelle, Ponchon Luc, Coelho Dylan, Bonhomme Frédéric, Braud Emmanuelle, Etheve-Quelquejeu Mélanie, Sargueil Bruno
Université Paris Cité, CNRS, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Paris, France.
Université Paris Cité, CNRS, Paris, France.
Commun Chem. 2025 Aug 12;8(1):244. doi: 10.1038/s42004-025-01627-7.
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 = 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.
甲基转移酶（MTases）是一类能够使蛋白质、DNA、RNA、脂质和小分子等生物分子甲基化的酶，大多使用S-腺苷-L-甲硫氨酸（SAM）作为甲基供体。MTases已成为有前景的药物靶点，SAM类似物被广泛用于研究它们在疾病中的作用以及开发有效的药物疗法。我们设计并合成了具有模仿甲硫氨酸侧链的方酰胺部分的稳定SAM类似物。这些化合物在两种人类m⁶A RNA甲基转移酶METTL3/14和METTL16上进行了测试。虽然这些SAM类似物不能支持催化活性，但它们对METTL3/14的活性表现出强大的抑制作用。令人惊讶的是，其中一些化合物表现出显著的效力（K = 3 nM）和特异性，这可能归因于方酰胺基序的独特性质。对接研究表明，它们与SAM类似，结合在METTL3/14辅因子口袋中，这使我们能够对催化机制提出新的假设。我们的合成方法扩展了SAM类似物的结构多样性，为开发选择性RNA甲基转移酶抑制剂奠定了基础。
