Engineering of spectator glycocalyx structures to evaluate molecular interactions at crowded cellular boundaries

Honigfort, Daniel J.; Zhang, Michelle; Verespy, Stephen; Godula, Kamil

doi:10.1039/c9fd00024k

Cited by 18 publications

(15 citation statements)

References 35 publications

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“…The efficiency of this “click” process resulted in a high frequency of glycosylated side-chains in close proximity to the PEO backbone, forcing the glycopolymers into extended conformations characteristic of mucins. 17,24 Seeking to isolate the biophysical properties of mucins from their glycan interactions, we modified our glycopolymers with glucose, a monosaccharide typically not found in mucin glycans ( Fig 1 ). This produced mucin mimetic “spectators” lacking Sia receptors for IAVs but able to tune the size and density of the glycocalyx.…”

Section: Resultsmentioning

confidence: 99%

Glycocalyx crowding with synthetic mucin mimetics strengthens interactions between soluble and virus-associated lectins and cell surface glycan receptors

Gagneux

et al. 2021

Preprint

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Membrane-associated mucins protect epithelial cell surfaces against pathogenic threats by serving as non-productive decoys that capture infectious agents and clear them from the cell surface and by erecting a physical barrier that restricts their access to target receptors on host cells. However, the mechanisms through which mucins function are still poorly defined due to a limited repertoire of tools available for tailoring their structure and composition in living cells with molecular precision. Using synthetic glycopolymer mimetics of mucins, we modeled the mucosal glycocalyx on red blood cells (RBC) and evaluated its influence on lectin (SNA) and virus (H1N1) adhesion to endogenous sialic acid receptors. The glycocalyx inhibited the rate of SNA and H1N1 adhesion in a size- and density-dependent manner, consistent with current view of the mucins as providing a protective shield against pathogens. Counterintuitively, increasing density of the mucin mimetics enhanced the retention of bound lectins and viruses. Careful characterization of SNA behavior at the RBC surface using a range of biophysical and imaging techniques revealed lectin-induced crowding and reorganization of the glycocalyx with concomitant enhancement in lectin clustering, presumably through the formation of a more extensive glycan receptor patch at the cell surface. Our findings indicate that glycan-targeting pathogens may exploit the biophysical and biomechanical properties of mucins to overcome the mucosal glycocalyx barrier.

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Section: Resultsmentioning

confidence: 99%

Glycocalyx crowding with synthetic mucin mimetics strengthens interactions between soluble and virus-associated lectins and cell surface glycan receptors

Gagneux

et al. 2021

Preprint

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“…Synthetic mucin obtained from post-polymerization glycosylation of reducing sugars by A) RAFT polymerization and glycosylation by hydrazine ligation, [86] B) RAFT polymerization and glycosylation by oxime ligation with reducing free sugars, [87,88] and C) glycosylation by CuAAC reaction with alkyne bearing sugars. [91] X = arbitrary reducing sugar.…”

Section: Post-polymerization Glycosylation Preparation Of Synthetic Mmentioning

confidence: 99%

“…More recently, Godula and co-workers employed anionic ring opening to polymerize the epoxide derivative, 2-(chloromethyl)oxirane, to synthesize an azide-terminated poly (epichlorohydrin) (pECH) polymer with a hydroxyl group on the opposing terminus (25) ( Figure 13C). [91] The azide terminal was functionalized with cholestanone via the CuAAC, and the chloromethyl sidechains were converted to azides for further glycosylation with 4-alkyne linked glycans (Glc, Gal, Fuc, Glc A) via the CuAAC. However, the glycosylation efficiency was not determined in this work.…”

Section: Post-polymerization Glycosylation Preparation Of Synthetic Mmentioning

confidence: 99%

Design and Synthesis of Mucin‐Inspired Glycopolymers

2020

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Mucins are bottlebrush biopolymers that are glycoproteins on the surfaces of cells and as hydrogels secreted inside and outside the body. Mucin function in biology includes cell‐cell recognition, signaling, protection, adhesion, and lubrication. Because of their attractive and diverse properties, mucins have recently become the focus of synthetic efforts by researchers who hope to understand and emulate these biomaterials. This review is focused on the development of methodologies for preparing mucin‐inspired synthetic oligomers and glycopolymers, including solid‐phase synthesis, polymerization of glycosylated monomers, and post‐polymerization grafting of glycans to polymer chains. How these synthetic mucins have been used in health applications is discussed. Natural mucins are formed from a conserved set of monomers that are combined into chains of different sequences and lengths to achieve materials with widely diverse properties. Adopting this design paradigm from natural mucins could lead to next‐generation bioinspired synthetic materials.

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“…This session started with Prof. Kamil Godula (University of California San Diego) telling the audience about the 'spectator glycocalyx.' 15 In addition to enabling the presentation of carbohydrate motifs on cellular surfaces, the glycocalyx provides an important physical barrier which regulates cell-cell interactions and mediates exchange across the cell membrane. In order to explore how the physical properties of the cellular interface effect carbohydrate recognition, his group synthesized a series of PEG-based analogues of mucin glycoproteins, with variable glycan composition.…”

Section: Session 3: Glycan Interactions On Glycocalyx Mimetic Surfacesmentioning

confidence: 99%

Highlights from Faraday Discussion 301: Nanolithography of Biointerfaces, London, UK, July 3–5 2019

Mahon

Huang

2019

Chem. Commun.

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Engineering of spectator glycocalyx structures to evaluate molecular interactions at crowded cellular boundaries

Abstract: Membrane engineering with bystander glycocalyx structures reveals altered protein–receptor association in crowded cell surface environments.

Cited by 18 publications

References 35 publications

Glycocalyx crowding with synthetic mucin mimetics strengthens interactions between soluble and virus-associated lectins and cell surface glycan receptors

Glycocalyx crowding with synthetic mucin mimetics strengthens interactions between soluble and virus-associated lectins and cell surface glycan receptors

Design and Synthesis of Mucin‐Inspired Glycopolymers

Highlights from Faraday Discussion 301: Nanolithography of Biointerfaces, London, UK, July 3–5 2019

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