It has been hypothesized that DENV needs DC-SIGN for attachment and enhancing infection of DC in cis and needs MR for internalization. In fact, cells expressing mutant DC-SIGN, lacking the internalization domain, are still susceptible for DENV infection because DC-SIGN can capture the pathogen. Interaction between DENV and DC-SIGN or MR is abrogated by deglycosylation of the DENV envelope and by EDTA or mannan, indicating that the interaction is carbohydrate dependent. DC-SIGN and MR have respectively 1 and 8 carbohydrate recognition domains responsible for pathogen recognition. Other pathogens recognized by DCSIGN and MR are HIV, HCV and human cytomegalovirus. These interactions are carbohydrate-dependent and are inhibited by various CBAs. In a previous report, we were the first to demonstrate the antiviral activity of the CBAs against DENV-2 in Raji/DC-SIGN cells and IL-4-treated monocytes. In the Cinoxacin present study, we studied the antiviral activity of these CBAs on the four DENV serotypes in primary MDDC, the most important target cells for DENV. A number of these CBAs proved about 100-fold 
more effective in inhibiting DENV infection in primary MDDC compared to the transfected Raji/DC-SIGN cell line. We also demonstrated that the mannose binding lectin HHA prevents DENV-2 binding to the host cell and acts less efficiently in the postbinding stage. HHA interacts with DENV and not with DC-SIGN on the target cell. The potency of HHA to inhibit attachment of DENV to Raji/DC-SIGN cells is Ginsenoside-Ro comparable to its inhibitory activity of the capture of HIV and HCV to Raji/DCSIGN + cells. CBAs could thus be considered as unique prophylactic agents. However, plant lectins are not orally bioavailable, sensitive for proteolytic cleavage and expensive to produce, they provide novel insights into the entry mechanism of DENV in human primary cells. The search for non-peptidic small molecules with CBA-like activity is therefore warranted. PRM-S, a derivate of the antibiotic PRM-A, acts as a CBA in terms of glycan recognition and exerts antiviral activity against HIV and SIV. The compound has high solubility and a high barrier for HIV resistance development. In MDDC, we observed a dose-dependent antiviral activity of PRM-S against DENV-2, comparable to the antiviral activity against HIV. In contrast, PRM-S exerted only weak antiviral activity in Raji/DCSIGN + cells. Accordingly, the antiviral potency of the other CBAs, HHA, GNA and UDA was higher in primary MDDC than in Raji/DC-SIGN + cells as well. This may be due to several celldependent specificities. First, Raji/DC-SIGN + cells are more susceptible for DENV infection compared to MDDC although the DC-SIGN expression level is comparable in the two cell-types. Although MDDC cultures contain a low amount of T-cells and B-cells, these cell types are not susceptible for DENV infection. Second, the entry process of DENV in Raji/DC-SIGN + cells and in MDDC is fundamentally different. In Raji/DCSIGN + cells, the entry process is mainly dependent on DC-SIGN. This is in contrast to MDDC, where unidentified cofactors for infection or DC-SIGN-independent entry pathways of the virus may be present. Although, whatever entry pathway in MDDC is employed by the virus, DENV infection is efficiently inhibited by CBAs. This indicates that the DENV entry in human cells is carbohydrate-dependent and that CBAs also inhibit DC-SIGNindependent entry pathways in MDDC. Consequently, the observed antiviral activity of the CBAs in human primary MDDC may be considered more relevant than in artificial constructed cell lines such as the Raji/DC-SIGN + cell line.