Nonreducing Sugar Scaffold Enables the Development of Immunomodulatory TLR4‐specific LPS Mimetics with Picomolar Potency

Abstract: Innate immune defense mechanisms against infection and cancer encompass the modulation of pattern recognition receptor (PRR)‐mediated inflammation, including upregulation of various transcription factors and the activation of pro‐inflammatory pathways important for immune surveillance. Dysfunction of PRRs‐mediated signaling has been implicated in cancer and autoimmune diseases, while the overactivation of PRRs‐driven responses during infection can lead to devastating consequences such as acute lung injury or sepsis. We used crystal structure‐based design to develop immunomodulatory lipopolysaccharide (LPS) mimetics targeting one of the ubiquitous PRRs, Toll‐like Receptor 4 (TLR4). Taking advantage of an exo‐anomeric conformation and specific molecular shape of synthetic nonreducing β,β‐diglucosamine, which was investigated by NMR, we developed two sets of lipid A mimicking glycolipids capable of either potently activating innate immune responses or inhibiting pro‐inflammatory signaling. Stereoselective 1,1′‐glycosylation towards fully orthogonally protected nonreducing GlcNβ(1↔1′)βGlcN followed by stepwise assembly of differently functionalised phosphorylated glycolipids provided biologically active molecules that were evaluated for their ability to trigger or to inhibit cellular innate immune responses. Two LPS mimetics, identified as potent TLR4‐specific inducers of the intracellular signaling pathways, serve as vaccine adjuvant‐ and immunotherapy candidates, while anionic glycolipids with TLR4‐inhibitory potential hold therapeutic promise for the management of acute or chronic inflammation.

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch

Verweise und Beziehungen

• Erschienen in: Nonreducing Sugar Scaffold Enables the Development of Immunomodulatory TLR4‐specific LPS Mimetics with Picomolar Potency ; day:21 ; month:08 ; year:2024 ; extent:13 ; Angewandte Chemie / International edition. International edition ; (21.08.2024) (gesamt 13)

Beteiligte, Orts- und Zeitangaben

• Urheber: Strobl, Sebastian ; Zucchetta, Daniele ; Vašíček, Tomáš ; Monti, Alessandro ; Ruda, Alessandro ; Widmalm, Göran ; Heine, Holger ; Zamyatina, Alla

Weitere Informationen

• DOI: 10.1002/anie.202408421
• URN: urn:nbn:de:101:1-2408221409384.681758625156
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 14.08.2025, 10:51 MESZ