Reaction of a Programmable Glycan Presentation of Glycodendrimersomes and Cells with Engineered Human Lectins To Show the Sugar Functionality of the Cell Surface

Kopitz, Jürgen; Xiao, Qi; Ludwig, Anna‐Kristin; Romero, Antonio; Michalak, Malwina; Sherman, Samuel E.; Zhou, Xuhao; Dazen, Cody; Vértesy, Sabine; Kaltner, Herbert; Klein, Michael L.; Gabius, Hans‐Joachim; Percéc, Virgil

doi:10.1002/ange.201708237

Cited by 7 publications

(10 citation statements)

References 66 publications

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“…Proteolytic Gal‐3 truncation to its CRD by matrix metalloproteinases may be a control mechanism that attenuates or resolves inflammation. This assumption inspires the idea that a multimeric Gal‐3 CRD construct (with active CRD or a mutant) may efficiently block CXCL12 activity in situ , while Gal‐1 oligomerization appears to increase aspects of its biomedical activity . The interaction of a lectin with a non‐glycan counterreceptor, together with such engineering, can thus have a biomedical potential .…”

Section: Discussionmentioning

confidence: 99%

Chemokines and galectins form heterodimers to modulate inflammation

Eckardt¹,

Miller

Blanchet³

et al. 2020

EMBO Reports

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Chemokines and galectins are simultaneously upregulated and mediate leukocyte recruitment during inflammation. Until now, these effector molecules have been considered to function independently. Here, we tested the hypothesis that they form molecular hybrids. By systematically screening chemokines for their ability to bind galectin‐1 and galectin‐3, we identified several interacting pairs, such as CXCL12 and galectin‐3. Based on NMR and MD studies of the CXCL12/galectin‐3 heterodimer, we identified contact sites between CXCL12 β‐strand 1 and Gal‐3 F‐face residues. Mutagenesis of galectin‐3 residues involved in heterodimer formation resulted in reduced binding to CXCL12, enabling testing of functional activity comparatively. Galectin‐3, but not its mutants, inhibited CXCL12‐induced chemotaxis of leukocytes and their recruitment into the mouse peritoneum. Moreover, galectin‐3 attenuated CXCL12‐stimulated signaling via its receptor CXCR4 in a ternary complex with the chemokine and receptor, consistent with our structural model. This first report of heterodimerization between chemokines and galectins reveals a new type of interaction between inflammatory mediators that can underlie a novel immunoregulatory mechanism in inflammation. Thus, further exploration of the chemokine/galectin interactome is warranted.

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Section: Discussionmentioning

confidence: 99%

Chemokines and galectins form heterodimers to modulate inflammation

Eckardt¹,

Miller

Blanchet³

et al. 2020

EMBO Reports

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“…IAJDs are stable for a long time after being stored in a chemistry laboratory at room temperature in air, while their DNPs are stable and remain active for at least 5 months at the normal refrigerator temperature of 5 °C [ 24 , 25 , 26 ]. The original architecture of one-component IAJDs [ 24 , 25 , 26 ] was inspired by the structure of amphiphilic Janus dendrimers (JDs) [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ], Janus glycodendrimers (JGDs) [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ], and sequence-defined JGDs [ 71 , 72 ] and will be discussed in more detail later.…”

Section: Resultsmentioning

confidence: 99%

“…This co-assembly process proceeds by the simple injection of the IAJD into the acidic buffer solution of mRNA. The IAJD concept was developed, as already mentioned in the early part of this paper, based on inspiration from research on amphiphilic Janus dendrimers (JDs) that self-assemble dendrimersomes (DS) [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ] and sequence-defined amphiphilic Janus glycodendrimers (JGD) that self-assemble glycodendrimersomes (GDSs) [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ].…”

Section: The Early Days Of Nucleic Acid Delivery and Their Evolution ...mentioning

confidence: 99%

Screening Libraries to Discover Molecular Design Principles for the Targeted Delivery of mRNA with One-Component Ionizable Amphiphilic Janus Dendrimers Derived from Plant Phenolic Acids

Atochina‐Vasserman

Maurya

et al. 2023

Pharmaceutics

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Viral and synthetic vectors to deliver nucleic acids were key to the rapid development of extraordinarily efficient COVID-19 vaccines. The four-component lipid nanoparticles (LNPs), containing phospholipids, PEG-conjugated lipids, cholesterol, and ionizable lipids, co-assembled with mRNA via a microfluidic technology, are the leading nonviral delivery vector used by BioNTech/Pfizer and Moderna to access COVID-19 mRNA vaccines. LNPs exhibit a statistical distribution of their four components when delivering mRNA. Here, we report a methodology that involves screening libraries to discover the molecular design principles required to realize organ-targeted mRNA delivery and mediate activity with a one-component ionizable multifunctional amphiphilic Janus dendrimer (IAJD) derived from plant phenolic acids. IAJDs co-assemble with mRNA into monodisperse dendrimersome nanoparticles (DNPs) with predictable dimensions, via the simple injection of their ethanol solution in a buffer. The precise location of the functional groups in one-component IAJDs demonstrated that the targeted organs, including the liver, spleen, lymph nodes, and lung, are selected based on the hydrophilic region, while activity is associated with the hydrophobic domain of IAJDs. These principles, and a mechanistic hypothesis to explain activity, simplify the synthesis of IAJDs, the assembly of DNPs, handling, and storage of vaccines, and reduce price, despite employing renewable plant starting materials. Using simple molecular design principles will lead to increased accessibility to a large diversity of mRNA-based vaccines and nanotherapeutics.

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“…Lectins, however, may find an Achilles heel on the virus surface. Stepwise refinements of tracing viral surface features through tissue lectins by mutational tuning, architecture engineering, and chimera design has potential to create variants with favorable properties (55)(56)(57).…”

Section: Discussionmentioning

confidence: 99%

From examining the relationship between (corona)viral adhesins and galectins to glyco-perspectives

Klein

Romero

Kaltner

et al. 2021

Biophysical Journal

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SignificanceThe sugary (carbohydrate glycan) coating of biological surfaces is important for binding and recognition. Lectins, a ubiquitous superfamily of proteins defined by presence of a carbohydrate recognition domain, enable bridging between biological surfaces. Evolution has led to distinct receptor classes. Galectins, lactose-binding proteins, form a family present in all animals. The discovery of structural similarity between virus attachment proteins, named adhesins, and mammalian galectins, most recently for the coronavirus spike protein, crucial for COVID-19 infection, indicates virus adhesins may have originated from galectins captured from the host genome. This hypothesis suggests that to counter viral threats one could develop therapeutics that inhibit contact between the viral (galectin-like) adhesion proteins and their cellular counterreceptors inspired by experience gleaned from studying galectins.

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Reaction of a Programmable Glycan Presentation of Glycodendrimersomes and Cells with Engineered Human Lectins To Show the Sugar Functionality of the Cell Surface

Cited by 7 publications

References 66 publications

Chemokines and galectins form heterodimers to modulate inflammation

Chemokines and galectins form heterodimers to modulate inflammation

Screening Libraries to Discover Molecular Design Principles for the Targeted Delivery of mRNA with One-Component Ionizable Amphiphilic Janus Dendrimers Derived from Plant Phenolic Acids

From examining the relationship between (corona)viral adhesins and galectins to glyco-perspectives

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