title: Steering Siglec-Sialic Acid Interactions on Living Cells using Bioorthogonal Chemistry.
abstract: Sialic acid sugars that terminate cell-surface glycans form the ligands for the sialic acid binding immunoglobulin-like lectin (Siglec) family, which are immunomodulatory receptors expressed by immune cells. Interactions between sialic acid and Siglecs regulate the immune system, and aberrations contribute to pathologies like autoimmunity and cancer. Sialic acid/Siglec interactions between living cells are difficult to study owing to a lack of specific tools. Here, we report a glycoengineering approach to remodel the sialic acids of living cells and their binding to Siglecs. Using bioorthogonal chemistry, a library of cells with more than sixty different sialic acid modifications was generated that showed dramatically increased binding toward the different Siglec family members. Rational design reduced cross-reactivity and led to the discovery of three selective Siglec-5/14 ligands. Furthermore, glycoengineered cells carrying sialic acid ligands for Siglec-3 dampened the activation of Siglec-3+monocytic cells through the NF-κB and IRF pathways.
authors.affiliation: Department of Radiation Oncology, Radiotherapy & OncoImmunology Laboratory, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Christian
authors.identifier: 0000-0001-7785-2920
authors.initials: C
authors.lastname: Büll
authors.affiliation: Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.
authors.forename: Torben
authors.initials: T
authors.lastname: Heise
authors.affiliation: Computational Discovery and Design Group, Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Niek
authors.initials: N
authors.lastname: van Hilten
authors.affiliation: Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.
authors.forename: Johan F A
authors.initials: JF
authors.lastname: Pijnenborg
authors.affiliation: Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.
authors.forename: Victor R L J
authors.initials: VR
authors.lastname: Bloemendal
authors.affiliation: Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.
authors.forename: Lotte
authors.initials: L
authors.lastname: Gerrits
authors.affiliation: Department of Radiation Oncology, Radiotherapy & OncoImmunology Laboratory, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Esther D
authors.initials: ED
authors.lastname: Kers-Rebel
authors.affiliation: Computational Discovery and Design Group, Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Tina
authors.initials: T
authors.lastname: Ritschel
authors.affiliation: Department of Radiation Oncology, Radiotherapy & OncoImmunology Laboratory, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA, Nijmegen, The Netherlands.|Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Martijn H
authors.initials: MH
authors.lastname: den Brok
authors.affiliation: Department of Radiation Oncology, Radiotherapy & OncoImmunology Laboratory, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Gosse J
authors.identifier: 0000-0002-6750-1665
authors.initials: GJ
authors.lastname: Adema
authors.affiliation: Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.
authors.forename: Thomas J
authors.identifier: 0000-0001-9141-8784
authors.initials: TJ
authors.lastname: Boltje
keywords: Siglecs; bioorthogonal chemistry; immunology; molecular modeling; sialic acids