Modulating receptor activity, immune response, and kinetic solubility : the impact of linker chemistry in conjugated NOD2/TLR4 agonists

Paradiso, Emiliano (avtor), Janež, Špela (avtor), Jakopin, Žiga (avtor)

Novel immunopotentiators are essential for advancing our understanding of immune receptor crosstalk and for addressing infectious diseases. Previous studies have suggested that coactivation of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and Toll-like receptor 4 (TLR4) can synergistically enhance the immune response. To investigate this synergy, we synthesized and evaluated a series of conjugated NOD2/TLR4 dual agonists comprising our in-house NOD2 agonist and two structurally distinct TLR4 agonists connected via flexible or rigid linkers. Our findings indicate that dual agonist activity toward both NOD2 and TLR4 is diminished upon conjugation. We also show that the linker chemistry significantly influences the kinetic solubility of these conjugates. Furthermore, the conjugates elicit distinct immunomodulatory effects in human primary peripheral blood mononuclear cells, characterized by a Th2-polarized cytokine response. These results provide insights into the structure–activity relationship of conjugated NOD2/TLR4 agonists and offer preliminary guidelines for tuning their solubility profiles.

• Jezik: Angleški jezik
• Ključne besede: agonists, conjugate acid-base pairs, ethyl groups, mixtures, solubility
• 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: 2025
• Št. strani: Str. 39060-39072
• Številčenje: Vol. 10, iss. 34
• PID: 20.500.12556/RUL-176560
• UDK: 544.351.3
• ISSN pri članku: 2470-1343
• DOI: 10.1021/acsomega.5c05358
• COBISS.SI-ID: 253244675
• Datum objave v RUL: 03.12.2025

Gradivo je del revije

• Naslov: ACS omega
• Skrajšan naslov: ACS omega
• Založnik: American Chemical Society
• ISSN: 2470-1343
• COBISS.SI-ID: 525873945

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: agonisti, konjugirani kislinsko-bazni pari, etilne skupine, zmesi, topnost, imunski odziv

Projekti

• Financer: ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
• Številka projekta: P1-0420
• Naslov: Napredna imunološka zdravila in celični pristopi v farmaciji

• Financer: ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
• Številka projekta: J3-4496
• Naslov: Adjuvansi naslednje generacije za mukozna cepiva