Sulfonylurea bioisosteres of sulfonic acid in JFD 00458-based ST6GAL1 inhibitors enhance membrane permeabilityKoraj, Natan (Avtor) Dangudubiyyam, Sushmaa (Avtor) Betances-Mora, Adelyn M. (Avtor) Faganeli, Ema (Avtor) Harduin-Lepers, Anne (Avtor) Angulo, Jesús (Avtor) Khanh Nguyễn, Tấn (Avtor) Bort-Griñó, María (Avtor) Hurtado Guerrero, Ramón (Avtor) Anderluh, Marko (Avtor) α−26-sialylatransferaseenzyme inhibitorglycosyltransferasesialyltransferaseST6GAL1 inhibitionSialyltransferases 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.20262026-10-14 09:59:32Članek v reviji189739sl