Explore by Category: Asialoglycoprotein receptor (ASGPR) | Siglecs | Mannose-6-phosphate Receptor | Influenza HAs | Mannose Receptor (CD206) | Galectins

Glycan Ligands for Targeting

Glycan ligands for targeting such as N-acetyl galactosamine (GalNAc), galactose, mannose, mannose-6-phosphate, sialosides, and others, play a pivotal role in the targeted delivery of therapeutics by exploiting their natural affinity for specific cell surface receptors. For example, GalNAc and galactose are ligands for the asialoglycoprotein receptor (ASGPR), also known as the Ashwell-Morell receptor, which is a C-type lectin expressed on the surface of hepatocytes in the liver. The use of GalNAc enables selective delivery of therapeutics such as oligonucleotides to hepatocytes. Similarly, sialylated glycans can target Siglec receptors found on immune cells, enabling selective delivery of therapeutics directly to these cells to treat immune cell related diseases without affecting other tissues. The mannose receptor, which is overexpressed on macrophages and dendritic cells, can be used for targeted delivery of vaccines and immunotherapies, enhancing immune responses against infections and tumors.

Glyco-engineered nanoparticles can be designed to display specific glycans or, alternatively, glycans can be directly attached to therapeutic molecules. This strategy exploits glycan-binding proteins to facilitate receptor-mediated endocytosis and improve cellular uptake which minimizes systemic side effects and maximizes therapeutic efficacy by ensuring that drugs are delivered precisely where they are needed. Furthermore, glycan-based drug delivery systems can enhance drug stability and prolong circulation time. Glycan modifications can help shield therapeutics from degradation and immune recognition, thereby increasing their half-life in the bloodstream and ensuring a sustained release of the therapeutic agent at the target site. These innovations in the Glycosciences significantly advance the precision and effectiveness of targeted hepatic & extra-hepatic drug delivery strategies.

Asialoglycoprotein receptor (ASGPR)

The asialoglycoprotein receptor (ASGPR), also known as the Ashwell-Morell receptor, is a C-type lectin found predominantly on the surface of hepatocytes in the liver. It binds to galactose and N-acetylgalactosamine (GalNAc) residues. ASGPR plays a crucial role in the endocytosis and clearance of glycoproteins that have had their terminal sialic residues removed which exposes the underlying galactose residues. Upon binding its ligand, ASGPR facilitates the internalization of the glycoprotein into the hepatocyte via receptor mediated endocytosis. The glycoprotein then enters the endo-lysosomal pathway for degradation. Removal of desialylated glycoproteins from the bloodstream helps to maintain serum glycoprotein homeostasis and prevent accumulation of potentially harmful glycoproteins.

The ASGPR has drawn extensive attention as a target for selective delivery of therapeutics to hepatocytes because of its expression pattern and endocytic properties. The field of oligonucleotide-based drug development has greatly benefited from the use of multivalent conjugates of GalNAc to target ASGPR for hepatic delivery of therapeutic oligonucleotides. Our various GalNAc products including tris-GalNAc conjugates can be directly coupled to therapeutic payloads using a variety of chemistries or alternatively GalNAc-lipid conjugates can be used to formulate liposomal nanoparticles for the targeted delivery of encapsulated payloads.

  • Galα

    Galα

    Galactose (Galα) ligands can be used to target drugs to hepatocytes in...

    Galα

  • Galβ

    Galβ

    Galactose (Galβ) ligands can be used to target drugs to hepatocytes in...

    Galβ

  • GalNAcα

    GalNAcα

    N-acetylgalactosamine (GalNAcα) ligands can be used to target drugs to hepatocytes in...

    GalNAcα

  • GalNAcβ

    GalNAcβ

    N-acetylgalactosamine (GalNAcβ) ligands can be used to target drugs to hepatocytes in...

    GalNAcβ

  • Tri-GalNAc

    Tri-GalNAc

    Tri-N-acetylgalactosamine (Tri-GalNAcβ) probes can be used to target drugs to hepatocytes in...

    Tri-GalNAc

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Siglecs

Siglecs (Sialic acid-binding immunoglobulin-type lectins) are a family of cell surface proteins primarily expressed on immune cells. They have critical functions in signaling, immune cell regulation, recognition of self-associated molecular patterns (SAMPs) and pathogens, and as immune checkpoint inhibitors. All Siglecs are characterized by their extracellular domain, which includes one or more immunoglobulin-like domains, and a single transmembrane region. The terminal most V-set extracellular domain is responsible for sialic acid recognition. Many Siglecs (e.g., Siglec-2, 3, 5-10) have a cytoplasmic tail that contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that induce strong inhibitory signaling. While other Siglecs (e.g., Siglec-14, -15, and -16) lack intracellular domains and instead have positively charged amino acid residues in the transmembrane region that associate with tyrosine-based activation motif (ITAMs) adapter proteins (e.g., DAP-12) leading to signal activation. Binding of Siglecs to sialylated ligands can lead to internalization via receptor mediated endocytosis. There is significant interest in targeting Siglecs due to their roles in autoimmune diseases, immune suppression in cancer, infectious diseases, and neurological disorders.

Though Siglecs recognize sialic acid (e.g., Neu5Ac or Neu5Gc), the different family members have varying specificity for the sialic acid linkage and underlying glycan structure. For example, while Siglec-1 primarily binds to Neu5Acα2-3Galβ1-4GlcNAc terminal glycan structures, human Siglec-2 (hCD22) binds to Neu5Acα2-6Galβ1-4GlcNAc. Others such as Siglec-8 require sulfation at the 6-O position of galactose - Neu5Acα2-3(6-OSO3-)Galβ1-4GlcNAc. Due to the overlap in specificity and the low mono-valent affinity of these natural ligands, selective, high-affinity Siglec ligands have been developed. SRL has a portfolio of sialylated ligands that can be conjugated directly to various diagnostic or therapeutic probes or Sialylated-PEG-lipid conjugates that can be used to form targeted liposomal nanoparticles (LNPs) for the delivery of encapsulated payloads to immune cells.

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Mannose-6-phosphate Receptor

The mannose-6-phosphate receptor (M6PR) is a transmembrane glycoprotein pivotal for the proper targeting of lysosomal enzymes to the lysosome, thereby ensuring cellular metabolic homeostasis. The glycan binding domain binds to mannose-6-phosphate (M6P) tagged lysosomal enzymes. The enzymes acquire M6P residues during the maturation in the Golgi apparatus. Upon binding M6P-tagged enzymes in the trans-Golgi network, M6PR mediates their transport to early endosomes. This targeting process is crucial for directing enzymes to lysosomes, where they participate in the degradation of various cellular substrates. Dysfunction or deficiency of M6PR can lead to lysosomal storage diseases (LSD), where undegraded materials accumulate within the cells due to impaired enzyme trafficking.

Therapeutic applications targeting M6PR primarily focus on utilizing its role in directing M6P tagged biomolecules to the lysosome. For instance, using enzyme replacement therapy (ERT) for the treatment of lysosomal storage diseases such as Gaucher or Pompe disease. Individuals with these diseases are either deficient in or have a dysfunctional specific lysosomal enzyme leading to the accumulation of substrates and subsequent cellular damage. Treatment with recombinant lysosomal enzymes that are modified with M6P residues helps to breakdown the accumulated substrates. Another innovative approach targeting M6PR involves the use of lysosome targeting chimeras (LYTACs). These molecules consist of two functional domains, one that binds specifically to cell surface proteins on target cells and another domain that contains an M6P tag for lysosomal targeting via M6PR. The bifunctional molecule enables internalization of the bound target proteins into cells and their subsequent trafficking to lysosomes for degradation. This approach offers a potent mechanism to eliminate disease-associated proteins related to neurodegenerative disorders, cancer, and viral infections.

We provide a variety of mannose-6-phosphate (M6P) and mannose-6-phosphonate (M6Pn) products including monovalent and trivalent constructs. These reagents can be equipped with a variety of linkers for direct conjugation to biomolecules such as recombinant enzymes or antibodies for targeting the lysosome.

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Influenza HAs

Influenza hemagglutinins (HAs) are glycoproteins found on the surface of type A and B influenza viruses. Influenza A viruses have 18 different hemagglutinin sub-types (H1 to H18). They play a critical role in the infection process by facilitating viral entry into host cells and are therefore significant targets for the immune system and antiviral therapies. The HA displayed on the virus surface is a heavily glycosylated spike-like structure composed of trimeric hemagglutinin molecules. The infection process is initiated by the binding of the HA to specific sialylated ligands expressed on the host cell. The receptor-binding site on the hemagglutinin determines the host specificity of the virus. The natural reservoir for influenza viruses is primarily aquatic birds, especially wild waterfowl such as ducks, geese, and shorebirds. Influenza viruses can also be found in other avian species, including domestic poultry like chickens and turkeys. The virus can also adapt and infect a wide range of mammals including, most notably, pigs and humans.

In general, all influenza HA bind to sialic acid, however, the linkage specificity of the HA is a key concern and is considered a species barrier that determines infectivity. Avian viruses bind to ligands where the sialic acid is α2,3-linked to an underlying galactose residue, for example, Neu5Acα2-3Galβ1-4GlcNAc found on N-linked glycans. HA from human adapted viruses preferentially bind to glycans with α2,6-linked sialic acid such as Neu5Acα2-6Galβ1-4GlcNAc found on N-linked glycans. A switch in specificity of avian HA from α2,3- to α2,6-linked sialosides is an indication that the virus has adapted to human-like receptors commonly found in the upper respiratory tract and is a concern for the potential development of highly pathogenic and pandemic viruses. In addition to the sialic acid linkage HAs also show differences in binding specificity based on the underlying glycan structure. For example, fucosylation and sulfation of the underlying LacNAc structure are known to affect HA binding. Most notably, however, is that contemporary human adapted HA have evolved to bind α2-6 sialylated poly-LacNAc extended structures found on N-linked glycans.

Determining the receptor specificity of HA is important to monitor for adaptation to human-type receptors which is believed necessary for the efficient transmission of avian influenza virus among humans. HA specificity can be readily determined from binding experiments using immobilized synthetic sialoside ligands in plate or array-based assays. SRL provides various α2,3- and α2,6-sialylated products that can be used to screen HA. These include linear and biantennary N-linked glycans with terminal sialylated LacNAc and poly-LacNAc extended structures. The sialoside ligands are functionalized with a variety of linkers including amines, NHS-activated esters, azides and alkynes, and biotin so they can be immobilized on a variety of platforms. We can also provide focused custom sialoside libraries.

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Mannose Receptor (CD206)

The mannose receptor (CD206) is a glycan binding protein primarily expressed on the surface of certain immune cells, including macrophages and dendritic cells. They are involved in the recognition and uptake of glycoproteins and glycolipids that bear terminal mannose, fucose, or N-acetylglucosamine (GlcNAc) residues. The mannose receptor plays critical roles in innate immunity, antigen presentation, and tissue homeostasis. For example, it recognizes and binds to pathogen-associated molecular patterns (PAMPs) present on the surface of pathogens such as bacteria, viruses, fungi, and parasites. This recognition leads to phagocytosis of the pathogens by macrophages, facilitating their clearance from the body. On dendritic cells, the mannose receptor is involved in the internalization and processing of glycosylated antigens for presentation to T cells which initiates the adaptive immune response against pathogens and for tolerance induction. In addition, the mannose receptor participates in maintaining tissue homeostasis by mediating the clearance of glycoproteins and glycolipids from the extracellular environment.

Mannose receptors are being explored as targets for vaccine development. Designing vaccines that utilize mannose receptor-mediated antigen uptake by dendritic cells can enhance antigen presentation and stimulate potent immune responses against infectious agents or tumor antigens. The mannose receptor on macrophages, can be targeted for drug delivery to sites of inflammation or infection. Drugs can be conjugated to ligands or encapsulated in liposomal nanoparticles (LNPs) displaying ligands of the mannose receptor to enhance uptake by macrophages, thereby improving therapeutic efficiency and minimizing off-target effects.

We have a portfolio of products that can be used to target the mannose receptor, including monosaccharides (mannose, fucose, or GlcNAc), Fucα1-2Gal (Blood group O), and high mannan N-linked glycans. These glycans can be equipped with a variety of linkers for conjugation and immobilization.

Galectins

Galectins are a family of soluble glycan-binding proteins characterized by their conserved carbohydrate recognition domain (CRD). They are known to bind β-galactose containing residues such as LacNAc (Galβ1-4GlcNAc) units found on glycoproteins and glycolipids. Glycan modifications such as sialylation and sulfation can affect Galectin binding. They are involved in a wide range of biological processes, including cell-cell and cell-matrix interactions, immune modulation, inflammation, apoptosis, and cancer progression. Galectins are classified into three main types based on their structure: (i) Prototype Galectins (e.g., Galectin-1, -2, -7, -10, -13, and -14) contain one CRD and are usually monomeric; (ii) Tandem repeat Galectins (e.g., Galectin-4, -8, -9, and -12) contain two CRDs connected by a linker peptide and often forming homodimers; (iii) Chimeric Galectins (e.g., Galectin-3) have a single CRD but contain an extended N-terminal domain that facilitates multimerization. Galectins are potential biomarkers for various diseases, including cancer and inflammatory disorders and targeting Galectins with glycans or glycan analogs shows promise in developing therapies for cancer, autoimmune diseases, and infections.

We have a portfolio of ligands that contain LacNAc and poly-LacNAc chains. These ligands are equipped with a variety of linkers for conjugation or immobilization.

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