Targeting the glycans of glycoproteins: a novel paradigm for antiviral therapy

Abstract

Several chronic viral infections (such as HIV and hepatitis C virus) are highly prevalent and are a serious health risk. The adaptation of animal viruses to the human host, as recently exemplified by influenza viruses and the severe acute respiratory syndrome coronavirus, is also a continuous threat. There is a high demand, therefore, for new antiviral lead compounds and novel therapeutic concepts. In this Review, an original therapeutic concept for suppressing enveloped viruses is presented that is based on a specific interaction of carbohydrate-binding agents (CBAs) with the glycans present on viral-envelope glycoproteins. This approach may also be extended to other pathogens, including parasites, bacteria and fungi.

Figure 1. Overview of the particular antiviral activities of carbohydrate-binding agents (CBAs).

CBAs have been shown to efficiently inhibit the infection of T cells and macrophages by cell-free HIV particles (a), syncytia formation between HIV-infected cells and uninfected T cells (b), the capture of HIV particles by dendritic cell (DC)-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing non-integrin (DC-SIGN)-expressing cells such as DCs (c), and DC-SIGN-captured HIV transmission to T cells (d). Exposure of CBAs to the virus in cell culture has also been shown to force the virus to delete part of the protective glycan shield that is present on its envelope glycoprotein gp120. It is assumed that such glycan deletions trigger an enhanced neutralizing antibody response to the previously hidden immunogenic epitopes of gp120 and possibly also a cellular immune response. Parts c and d reproduced with permission from Ref. © (2006) University of Amsterdam. CCR5, chemokine receptor 5; LFA-1, lymphocyte function-associated antigen 1.

Figure 2. Structures of different N-glycan types.

Examples of the structural composition of high-mannose-type N-glycans. a | Tri-antennary complex-type N-glycans. b | Hybrid-type N-glycans. c | High-mannose-type N-glycans that are abundantly present on the envelope glycoprotein gp120 of HIV, but are rare on mammalian glycoproteins. Besides high-mannose-type N-glycans, the complex-type and hybrid-type N-glycans are also present on gp120. Asn, asparagine; Fuc, fucose; Gal, Galactose; GlcNAc, N-acetylglucosamine; Man, mannose; SA, sialic acid; Ser, serine; Thr, threonine; X, any amino acid except proline.

Figure 3. Low-size non-peptidic carbohydrate-binding antigens (CBAs).

Structural formulae of the calcium-dependent mannose-binding pradimicin A (a) and benanomicin A (b) antibiotic CBAs that are produced by Actinomadura hibiscus and Actinomadura spadix, respectively. Red represents the D-alanine moiety; black represents the dihydrobenzonaphtacenequinone core; green represents the carbohydrate part of the molecule.

Figure 4. Molecular interactions of carbohydrate-binding agents (CBAs) with carbohydrate oligomers.

a | The terminal mannose (Man) of Manα1–3Man is complexed to liver MBP–C (Protein Data Bank (PDB) ID 1kza). Calcium is depicted as a purple sphere, with coordinating residues in stick representation. The amino-acid residue Val194 (in orange) participates in van der Waals interactions. The calcium coordination and hydrogen bonds between protein and carbohydrate (blue) are shown as green spheres. b | Ribbon diagram of dendritic cell (DC)-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing non-integrin (DC-SIGN) complexed with Man₃ −(N-acetylglucosamine)₂ (Man₃GlcNAc₂) (PDB ID 1k9i). Calcium is shown as a green sphere, whereas the carbohydrate is shown in a yellow stick representation. The calcium coordination is shown in detail, with the hydrogen bonds to important coordinating residues shown as dotted spheres. The gray sphere represents a calcium site of another carbohydrate-recognition domain. c | Hydrogen bonding, van der Waals interactions and aromatic ring stacking of GlcNAc₃, with the GlcNAc-specific lectin from Urtica dioica (UDA) (PDB ID 1ehh). Two isolectin VI molecules are shown in blue and green. Dotted lines are hydrogen-bonding contacts between UDA and GlcNAc₃. Sugar residues are labelled with A, B, and C from the non-reducing end. d | Hydrogen-bonding pattern and van der Waals contacts of the Narcissus psuedonarcissus lectin 7 (NPL7) carbohydrate-binding domain complexed to Manα(1– 3)Man (PDB ID 1npl). The mannose residue in the main binding pocket is shown in bold lines, with the hydrogen bonds depicted as dotted lines and van der Waals contacts as purple lines. MBP-C, mannose-binding protein C. Panel a reproduced with permission from Ref. © (2005) Elsevier Science. Panel b reproduced with permission from Ref. © (2001) American Association for the Advancement of Science. Panel c reproduced with permission from Ref. © (2000) Elsevier Science. Panel d reproduced with permission from Ref. © (1999) Elsevier Science.

Figure 5. The HIV envelope glycoprotein gp120.

Ribbon diagrams showing the 24 putative N-glycosylation sites (coloured circles) in the HIV-1(III_B) envelope glycoprotein gp120 according to Kwong et al. and Leonard et al. a | High-mannose-type (green) and complex or hybrid-type (yellow) glycans. b | The red circles indicate the deleted N-glycosylation sites that appear under pressure from carbohydrate-binding agents (CBAs) (for example, Galanthus nivalis agglutinin (GNA), Hyppeastrum hybrid agglutinin (HHA), Urtica dioica agglutinin (UDA), cyanovirin-N (CV-N), pradimicin A (PRM-A) and the monoclonal antibody 2G12) in more than 30 different mutant virus isolates. The green circles represent glycosylation sites that have not yet been found to be deleted under CBA pressure. Images courtesy of Ir. K. François and M. Froeyen, Rega Institute, Leuven, Belgium.