Broad Antiviral Activity of Carbohydrate-Binding Agents against the Four Serotypes of Dengue Virus in Monocyte-Derived Dendritic Cells

Abstract

BackgroundDendritic cells (DC), present in the skin, are the first target cells of dengue virus (DENV). Dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) is present on DC and recognizes N-glycosylation sites on the E-glycoprotein of DENV. Thus, the DC-SIGN/E-glycoprotein interaction can be considered as an important target for inhibitors of viral replication. We evaluated various carbohydrate-binding agents (CBAs) against all four described serotypes of DENV replication in Raji/DC-SIGN+ cells and in monocyte-derived DC (MDDC).Methodology/Principal FindingsA dose-dependent anti-DENV activity of the CBAs Hippeastrum hybrid (HHA), Galanthus nivalis (GNA) and Urtica dioica (UDA), but not actinohivin (AH) was observed against all four DENV serotypes as analyzed by flow cytometry making use of anti-DENV antibodies. Remarkably, the potency of the CBAs against DENV in MDDC cultures was significantly higher (up to 100-fold) than in Raji/DC-SIGN+ cells. Pradimicin-S (PRM-S), a small-size non-peptidic CBA, exerted antiviral activity in MDDC but not in Raji/DC-SIGN+ cells. The CBAs act at an early step of DENV infection as they bind to the viral envelope of DENV and subsequently prevent virus attachment. Only weak antiviral activity of the CBAs was detected when administered after the virus attachment step. The CBAs were also able to completely prevent the cellular activation and differentiation process of MDDC induced upon DENV infection.Conclusions/SignificanceThe CBAs exerted broad spectrum antiviral activity against the four DENV serotypes, laboratory-adapted viruses and low passage clinical isolates, evaluated in Raji/DC-SIGN+ cells and in primary MDDC.

Basic chemokine-derived glycosaminoglycan binding peptides exert antiviral properties against dengue virus serotype 2, herpes simplex virus-1 and respiratory syncytial virus

“…Examples of binding and entry inhibitors are maraviroc [6;7], a chemokine receptor antagonist preventing the entry of HIV, and carbohydrate-binding agents that bind to glycoproteins on the virus surface thereby preventing infection with dengue virus (DENV) [8]. DENV is one of the most important emerging viruses in tropical and subtropical countries with 2.5 billion people at risk to get infected and every year more than 50 million clinical cases of DENV infections [9].…”

Broad Antiviral Activity of Carbohydrate-Binding Agents Against Dengue Virus Infection

“…Again, DC-SIGN expression on MDDC renders cells susceptible for DENV in contrast to monocytes ( Figure 7A, B). MR is also present on monocyte-derived DC (MDDC) and anti-MR antibodies can inhibit DENV infection, although to a lesser extent than anti-DC-SIGN antibodies do ( Figure 7C) [61]. Furthermore, the combination of anti-DC-SIGN and anti-MR antibodies was even more effective in inhibiting DENV infection.…”

“…This activation is induced by TNF-and IFN-secreted by DENV-infected DC [40,89,90]. Instead, Alen et al observed an upregulation of the costimulatory molecules CD80 and CD86 and a downregulation of DC-SIGN and MR on the total (uninfected and infected) DC population following DENV infection [61]. This could indicate that the DC are activated and can interact with naive T-cells and subsequently activate the immune system resulting in increased vascular permeability and fever.…”

“…PRM-S, a highly soluble non-peptidic small-size carbohydrate-binding antibiotic is a potential new lead compound in HIV therapy, since PRM-S efficiently inhibits HIV replication and prevents capture of HIV to DC-SIGN + cells [91]. PRM-S also inhibited dose-dependently DENV-2 replication in MDDC but had only a weak antiviral activity in Raji/DC-SIGN + cells [61]. Actinohivin (AH), a small prokaryotic peptidic lectin containing 114 amino acids, exhibits also anti-HIV-1 activity by recognizing high-mannose-type glycans on the viral envelope [92].…”

Flavivirus Entry Inhibitors

“…68,69 However, plant lectins are not orally bioavailable, sensitive for proteolytic cleavage, and expensive to produce. These shortcomings pose a significant challenge with respect to their development.…”