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

WAWRZINEK, ROBERT; WAMHOFF, EIKE-CHRISTIAN; LEFEBRE, JONATHAN; RENTZSCH, MAREIKE; BACHEM, GUNNAR; DOMENICONI, GARY; SCHULZE, JESSICA; FUCHSBERGER, FELIX F.; ZHANG, HENGXI; MODENUTTI, CARLOS; SCHNIRCH, LENNART; MARTI, MARCELO A.; SCHWARDT, OLIVER; BRÄUTIGAM, MARIA; GUBERMAN, MÓNICA; HAUCK, DIRK; SEEBERGER, PETER H.; SEITZ, OLIVER; TITZ, ALEXANDER; ERNST, BEAT; RADEMACHER, CHRISTOPH

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

AMER CHEMICAL SOC

Año: 2021 vol. 143 p. 18977 - 18988

0002-7863

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.