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

Koraj, 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)

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.

• Jezik: Angleški jezik
• Ključne besede: α−2, 6-sialylatransferase, enzyme inhibitor, glycosyltransferase, sialyltransferase, ST6GAL1 inhibition
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2026
• Št. strani: 9 str.
• Številčenje: Vol. 21, iss. 16, art. e70465
• PID: 20.500.12556/RUL-189739
• UDK: 615.4:54:616-097
• ISSN pri članku: 1860-7187
• DOI: 10.1002/cmdc.70465
• COBISS.SI-ID: 289094147
• Datum objave v RUL: 14.10.2026

Gradivo je del revije

• Naslov: ChemMedChem
• Skrajšan naslov: ChemMedChem
• Založnik: Wiley-VCH-Verl..
• ISSN: 1860-7187
• COBISS.SI-ID: 519053337

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: α−2, 6-sialilatransferaza, zaviralec encima, glikoziltransferaza, sialiltransferaza, zaviralci ST6GAL1, imunski sistem, farmacevtska kemija