A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN

Christoph Johannes Heinrich Rademacher (Korresp. Autor*in), Robert Wawrzinek, Eike-Christian Wamhoff, Jonathan Lefebre, Mareike Rentzsch, Gunnar Bachem, Gary Domeniconi, Jessica Schulze, Felix Franz Robert Fuchsberger, Zhang Hengxi, Carlos Modenutti, Lennart Schnirch, Marcelo A. Marti, Oliver Schwardt, Maria Bräutigam, Monica Guberman, Dirk Hauck, Peter H. Seeberger, Oliver Seitz, Alexander TitzBeat Ernst

Veröffentlichungen: Beitrag in FachzeitschriftArtikelPeer Reviewed

Abstract

Dendritic cells (DC) are antigen-presenting cells coordinating the interplay of the innate and the adaptive immune response. The endocytic C-type lectin receptors DC-SIGN and Langerin display expression profiles restricted to distinct DC subtypes and have emerged as prime targets for next-generation immunotherapies and anti-infectives. Using heteromultivalent liposomes copresenting mannosides bearing aromatic aglycones with natural glycan ligands, we serendipitously discovered striking cooperativity effects for DC-SIGN(+) but not for Langerin(+) cell lines. Mechanistic investigations combining NMR spectroscopy with molecular docking and molecular dynamics simulations led to the identification of a secondary binding pocket for the glycomimetics. This pocket, located remotely of DC-SIGN's carbohydrate bindings site, can be leveraged by heteromultivalent avidity enhancement. We further present preliminary evidence that the aglycone allosterically activates glycan recognition and thereby contributes to DC-SIGN-specific cell targeting. Our findings have important implications for both translational and basic glycoscience, showcasing heteromultivalent targeting of DCs to improve specificity and supporting potential allosteric regulation of DC-SIGN and CLRs in general.

OriginalspracheEnglisch
Seiten (von - bis)18977-18988
Seitenumfang12
FachzeitschriftJournal of the American Chemical Society
Jahrgang143
Ausgabenummer45
DOIs
PublikationsstatusVeröffentlicht - 17 Nov. 2021

ÖFOS 2012

  • 301207 Pharmazeutische Chemie

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