Journal Article

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

Balzarini, Jan

2007

Overview

Key Points Glycans that are present on glycoproteins often have a pivotal role in protein folding, trafficking and protection against degradation, the efficient operation of the innate immune system and, as in the case of pathogens such as HIV, escape by the immune system. There exists a wide range of carbohydrate-binding agents (CBAs), including lectins and synthetic small-size non-peptidic agents, and their molecular interactions with carbohydrates are well described. A number of CBAs, with a preference for mannose and/or N -acetylglucosamine (GlcNAc) recognition have been shown to inhibit HIV infections by blocking the viral entry process. They have also been shown to be active against other viruses such as human hepatitis C virus (HCV), coronavirus and influenza virus. When HIV is exposed to CBAs, virus escape eventually occurs predominantly by deleting its glycans on the viral envelope glycoprotein gp120. It has been shown that such mutant virus strains have an increased sensitivity to neutralizing antibodies. Numerous other pathogens, including HCV, bacteria such as Mycobacterium tuberculosis and Helicobacter pylori , parasites such as Leishmania spp. or fungi such as Aspergillus spp. and Candida spp., efficiently use the C-type lectin dendritic-cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) present on DCs for transmission and/or immune suppression. These pathogens may represent prime candidate compounds that can be exposed to CBAs in an attempt to interrupt the infection or transmission process in the host. CBA therapy of HIV (and possibly other pathogens) may represent a therapeutic approach with a dual mechanism of action: the direct inhibition of virus capture, transmission and entry into its target cells; and the recruitment of the immune system after glycan deletions occur under CBA pressure, uncovering previously hidden immunogenic epitopes on the viral envelope. Carbohydrate-binding agents (CBAs) are a family of diverse molecules that can bind to specific glycan structures on viruses or target cells. Jan Balzarini describes a new antiviral mechanism that is based on the specific interaction of CBAs with the glycans that are present on viral-envelope glycoproteins. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Antiviral agents / Antiviral Agents - metabolism / Antiviral Agents - pharmacology / Bacterial Proteins - metabolism / Bacterial Proteins - pharmacology / Binders (materials) / Binding / Biomedical and Life Sciences / Carbohydrate Metabolism / Carbohydrates / Cell adhesion / Coronaviruses / DC-SIGN protein / Dendritic cells / Disease transmission / Enzymes / Epitopes / Genetic aspects / Glycan / Glycoprotein gp120 / Glycoproteins / Health risks / Hepatitis / Hepatitis C / Hepatitis C virus / HIV / HIV Envelope Protein gp120 - chemistry / HIV Infections - drug therapy / HIV Infections - virology / HIV-1 - drug effects / Human immunodeficiency virus / Humans / Immune system / Immunogenicity / Infections / Infectious Diseases / Innate immunity / Intercellular adhesion molecule 3 / Lectins / Life Sciences / Lymphocytes / Mannose / Medical Microbiology / Microbiology / Models, Molecular / Molecular interactions / N-Acetylglucosamine / Parasites / Parasitology / Pathogens / Peptides / Physiological aspects / Plant Proteins - metabolism / Plant Proteins - pharmacology / Polysaccharides / Polysaccharides - chemistry / Polysaccharides - metabolism / Prevention / Protein folding / Protein transport / Proteins / review-article / SARS coronavirus / Severe acute respiratory syndrome / Viral Envelope Proteins - chemistry / Viral Envelope Proteins - metabolism / Viral infections / Viral vaccines / Virology / Virus diseases / Virus Diseases - drug therapy / Virus Diseases - virology / Viruses / Viruses - drug effects / Viruses - metabolism