Sulfonylurea bioisosteres of sulfonic acid in JFD 00458-based ST6GAL1 inhibitors enhance membrane permeability

Koraj, Natan (author), Dangudubiyyam, Sushmaa (author), Betances-Mora, Adelyn M. (author), Faganeli, Ema (author), Harduin-Lepers, Anne (author), Angulo, Jesús (author), Khanh Nguyễn, Tấn (author), Bort-Griñó, María (author), Hurtado Guerrero, Ramón (author), Anderluh, Marko (author)

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.

• Language: English
• Keywords: α−2, 6-sialylatransferase, enzyme inhibitor, glycosyltransferase, sialyltransferase, ST6GAL1 inhibition
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: 9 str.
• Numbering: Vol. 21, iss. 16, art. e70465
• PID: 20.500.12556/RUL-189739
• UDC: 615.4:54:616-097
• ISSN on article: 1860-7187
• DOI: 10.1002/cmdc.70465
• COBISS.SI-ID: 289094147
• Publication date in RUL: 14.10.2026

Record is a part of a journal

• Title: ChemMedChem
• Shortened title: ChemMedChem
• Publisher: Wiley-VCH-Verl..
• ISSN: 1860-7187
• COBISS.SI-ID: 519053337

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: α−2, 6-sialilatransferaza, zaviralec encima, glikoziltransferaza, sialiltransferaza, zaviralci ST6GAL1, imunski sistem, farmacevtska kemija