An analogue of the antibiotic teicoplanin prevents flavivirus entry in vitro.

Tine De Burghgraeve,Suzanne J F Kaptein,Maria Preobrazhenskaya,Johan Neyts,Jolanda M Smit,Andrea V Gamarnik,Nilda V Ayala-Nunez,Xavier De Lamballerie,Svetlana S Printsevskaya,Michael Jacobs,Boris Pastorino,Juan A Mondotte

doi:10.1371/journal.pone.0037244

Abstract

There is an urgent need for potent inhibitors of dengue virus (DENV) replication for the treatment and/or prophylaxis of infections with this virus. We here report on an aglycon analogue of the antibiotic teicoplanin (code name LCTA-949) that inhibits DENV-induced cytopathic effect (CPE) in a dose-dependent manner. Virus infection was completely inhibited at concentrations that had no adverse effect on the host cells. These findings were corroborated by quantification of viral RNA levels in culture supernatant. Antiviral activity was also observed against other flaviviruses such as the yellow fever virus and the tick-borne encephalitis virus (TBEV). In particular, potent antiviral activity was observed against TBEV. Time-of-drug-addition experiments indicated that LCTA-949 inhibits an early stage in the DENV replication cycle; however, a virucidal effect was excluded. This observation was corroborated by the fact that LCTA-949 lacks activity on DENV subgenomic replicon (that does not encode structural proteins) replication. Using a microsopy-based binding and fusion assay employing DiD-labeled viruses, it was shown that LCTA-949 targets the early stage (binding/entry) of the infection. Moreover, LCTA-949 efficiently inhibits infectivity of DENV particles pre-opsonized with antibodies, thus potentially also inhibiting antibody-dependent enhancement (ADE). In conclusion, LCTA-949 exerts in vitro activity against several flaviviruses and does so (as shown for DENV) by interfering with an early step in the viral replication cycle.

Highlights

The genus flavivirus comprises several pathogens, including dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), tick-borne encephalitis virus (TBEV) and Japanese encephalitis virus (JEV)
LCTA-949 is an in vitro inhibitor of flavivirus replication The effect of LCTA-949 (Figure 1) on the in vitro infection of a selection of flaviviruses was evaluated in cytopathic effect (CPE)-reduction assays and in virus yield reduction assays
The antiviral effect of LCTA-949 was further confirmed in virus yield reduction assays [EC50 value of 6.9 mM62.9 mM for DENV-2 and 5.163.1 mM for YFV-17D]; ribavirin was included as a reference molecule (Figure 3)

Summary

Introduction

The genus flavivirus (family Flaviviridae) comprises several pathogens, including dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), tick-borne encephalitis virus (TBEV) and Japanese encephalitis virus (JEV). Antibodies have been found to enhance viral entry into Fc-c-receptor-bearing cells and to alter the antiviral immune response, leading to increased virus particle production and subsequent immune activation. During heterologous re-infection, cross-reactive antibodies have been implicated to enhance viral replication leading to a higher infected cell mass and increased viral burden. There is neither a vaccine nor a specific antiviral therapy available [3] This is the case for YFV that, together with DENV, is a leading cause of hemorrhagic fever worldwide, a highly efficacious vaccine is available [5]. There is, as is the case for most of the other flaviviruses, no antiviral drug available for the treatment of YFV infections

Methods

Results

Conclusion