Multivalent SO4-3-Galactose Glycopolymers Define a Structural Threshold for CD206 Endocytic Inhibition
9 affiliations
- 1Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, Padova, Italy, 35131
- 2School of Pharmacy
- 3University of Nottingham
- 4Department of Chemistry
- 5University of Warwick
- 6School of Medicine
- 7University of Central Lancashire
- 8Department of Surgery, Oncology and Gastroenterology, University of Padova, Via V. Gallucci 3, Padova, Italy, 35121
- 9School of Life Sciences
Abstract
The Mannose Receptor (CD206) is a critical endocytic receptor involved in immune regulation and various pathologies, yet it remains largely unexplored as a therapeutic target due to the lack of specific modulators. We recently reported that multivalent SO 4 -3-Galactose (SO 4 -3-Gal) glycopolymers inhibit CD206 by blocking its recycling to the cell surface, but the role of ligand valency in this process was undefined. Here, using a monovalent SO4-3-Gal ligand together with a library of SO 4 -3-Gal glycopolymers spanning valencies from 6.5 to 211 – the latter synthesised via a new, scalable, metal-free aqueous RAFT route amenable to multigram production – we establish for the first time a quantitative, biphasic relationship between valency and CD206 inhibitory potency, with a steep increase up to a valency of ~28 SO 4 -3-Gal units followed by a shallower plateau, which may suggest a threshold-dependent, ligandinduced receptor clustering mechanism. Critically, these glycopolymers are non-cytotoxic, leave LPS-induced macrophage cytokine production (IL-6, IL-10, TNF-α) unaltered, and – as shown by bulk RNA sequencing of human macrophages – induce no detectable changes to the macrophage transcriptome, at baseline or upon LPS stimulation, demonstrating that CD206 blockade occurs without detectable perturbation of macrophage inflammatory responses or transcriptional profiles under the conditions tested.
Related
- Structural control of Fe(II)-based multivalent glycan assemblies enables intramolecular avidity and ultra-high-affinity binding
- Rationally designed tunable amphiphilic glycopolymers for safe and effective vaccine adjuvanticity
- Physicochemical and Structural Determinants of BACE1-Selective Inhibition: An Integrative Modeling Study using A Combined Ligand-and Structure-Based Approach
- Structural Mechanism of Filamentation Induced Dampening of GTP Inhibition of Glutamate Dehydrogenase
- Design and Synthesis of New Derivatives of Alkaloid Lupinine: Structural Characterization, Acetylcholinesterase Inhibition Evaluation, and Molecular Modeling Study
BibTeX
@misc{mastrotto2026multivalent,
title = {{Multivalent SO4-3-Galactose Glycopolymers Define a Structural Threshold for CD206 Endocytic Inhibition}},
author = {Francesca Mastrotto and Greta Bellio and Alexandre Blanchard and Gokhan Yilmaz and Sirina Muntaka and Enrico Gaffo and Stefania Bortoluzzi and Joshua Petch and David Onion and Darryl Jackson and Luisa Martinez-Pomares and Giuseppe Mantovani},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15009464/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009464/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Multivalent SO4-3-Galactose Glycopolymers Define a Structural Threshold for CD206 Endocytic Inhibition
AU - Francesca Mastrotto
AU - Greta Bellio
AU - Alexandre Blanchard
AU - Gokhan Yilmaz
AU - Sirina Muntaka
AU - Enrico Gaffo
AU - Stefania Bortoluzzi
AU - Joshua Petch
AU - David Onion
AU - Darryl Jackson
AU - Luisa Martinez-Pomares
AU - Giuseppe Mantovani
PY - 2026
DA - 2026/09/24
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009464/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009464/v1
AB - The Mannose Receptor (CD206) is a critical endocytic receptor involved in immune regulation and various pathologies, yet it remains largely unexplored as a therapeutic target due to the lack of specific modulators. We recently reported that multivalent SO 4 -3-Galactose (SO 4 -3-Gal) glycopolymers inhibit CD206 by blocking its recycling to the cell surface, but the role of ligand valency in this process was undefined. Here, using a monovalent SO4-3-Gal ligand together with a library of SO 4 -3-Gal glycopolymers spanning valencies from 6.5 to 211 – the latter synthesised via a new, scalable, metal-free aqueous RAFT route amenable to multigram production – we establish for the first time a quantitative, biphasic relationship between valency and CD206 inhibitory potency, with a steep increase up to a valency of ~28 SO 4 -3-Gal units followed by a shallower plateau, which may suggest a threshold-dependent, ligandinduced receptor clustering mechanism. Critically, these glycopolymers are non-cytotoxic, leave LPS-induced macrophage cytokine production (IL-6, IL-10, TNF-α) unaltered, and – as shown by bulk RNA sequencing of human macrophages – induce no detectable changes to the macrophage transcriptome, at baseline or upon LPS stimulation, demonstrating that CD206 blockade occurs without detectable perturbation of macrophage inflammatory responses or transcriptional profiles under the conditions tested.
ER -