20.500.12556/RUL-189739 Sulfonylurea bioisosteres of sulfonic acid in JFD 00458-based ST6GAL1 inhibitors enhance membrane permeability Sialyltransferases catalyze the transfer of sialic acid to glycoconjugates within the Golgi apparatus, generating cell-surface sialoglycans that regulate cell–cell and immune communication. This process can be modulated by inhibiting α−2,6-sialyltransferase 1 (ST6GAL1), one of the most important sialyltransferases. Most β-galactoside ST6GAL1 inhibitors are polar CMP-Neu5Ac derivatives with limited membrane permeability, a limitation shared by the noncarbohydrate inhibitor JFD 00458. Here, we designed JFD 00458 analogs to improve permeability while maintaining ST6GAL1 inhibition and direct target engagement. Incorporation of sulfonic-acid bioisosteres, particularly sulfonylureas, improved passive permeability, as measured by parallel artificial membrane permeability assay, with the best analog reaching log(P_app [cm/s]) = −4.3. Potency was also improved in an expanded series of sulfonylureas, with the best inhibitor displaying an IC$_{50}$ of 1.9 µM. Microscale thermophoresis confirmed direct ST6GAL1 binding, with similar apparent K$_d$ values of approximately 22–25 µM for JFD 00458 and the optimized sulfonylureas. Saturation transfer difference NMR identified the substituted phenoxy phenyl core as a common ST6GAL1-contacting epitope, while closer contacts from the sulfonylurea-linked aromatic substituents in 6d and 6e were associated with the highest inhibitory potency across the series. These results establish sulfonylureas as membrane-permeable sulfonic-acid bioisosteres and provide a structure–activity framework for further ST6GAL1 inhibitor optimization. α−2 6-sialylatransferase enzyme inhibitor glycosyltransferase sialyltransferase ST6GAL1 inhibition α−2 6-sialilatransferaza zaviralec encima glikoziltransferaza sialiltransferaza zaviralci ST6GAL1 imunski sistem farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2026-10-14 09:59:32 2026-10-14 09:59:40 2026-10-15 04:13:23 0000-00-00 00:00:00 2026 0 0 9 str. iss. 16, art. e70465 Vol. 21 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54:616-097 1860-7187 10.1002/cmdc.70465 289094147 ChemMedChem_-_2026_-_Koraj_-_Sulfonylurea_Bioisosteres_of_Sulfonic_Acid_in_JFD_00458‐Based_ST6GAL1_Inhibitors_Enhance.pdf ChemMedChem_-_2026_-_Koraj_-_Sulfonylurea_Bioisosteres_of_Sulfonic_Acid_in_JFD_00458‐Based_ST6GAL1_Inhibitors_Enhance.pdf 1 3A285AB3EAE09DA4587073FDD22E7192 63a9a668242230edc7ca1838ad197de939b071b76b3a27db5335272df1b8c0b6 864d7469-c7a6-11f1-8bc5-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=250511 https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.70465 1 1036d987-c7a5-11f1-8bc5-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=250510 Fakulteta za farmacijo 0 0 0