Quinic acid derivatives inhibit dengue virus replication in vitro

Abstract

BackgroundDengue is the most prevalent arboviral disease in tropical and sub-tropical areas of the world. The incidence of infection is estimated to be 390 million cases and 25,000 deaths per year. Despite these numbers, neither a specific treatment nor a preventive vaccine is available to protect people living in areas of high risk.ResultsWith the aim of seeking a treatment that can mitigate dengue infection, we demonstrated that the quinic acid derivatives known as compound 2 and compound 10 were effective against all four dengue virus serotypes and safe for use in a human hepatoma cell line (Huh7.5). Both compounds were non-virucidal to dengue virus particles and did not interfere with early steps of the dengue virus life cycle, including binding and internalization. Experiments using a replicon system demonstrated that compounds 2 and 10 impaired dengue virus replication in Huh7.5 cells. Additionally, the anti-dengue virus effects of the quinic acid derivatives were preserved in human peripheral blood mononuclear cells.ConclusionsTaken together, these data suggest that quinic acid derivatives represent a novel chemical class of active compounds that could be used to combat dengue virus infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-015-0443-9) contains supplementary material, which is available to authorized users.

Taraxacum officinale and Urtica dioica extracts inhibit dengue virus serotype 2 replication in vitro

“…An important parameter to consider is the selectivity index (SI), which ranged from 5.59 and 9.43 for the extracts or fractions. These values are similar to other reports of natural products with some anti-dengue activity [ 18 , 19 , 47 , 52 , 53 ]. SI represents the relative effectiveness of a product in inhibiting viral replication compared to inducing cell citotoxicity.…”

“…Multiple studies have reported the discovery or obtaining of compounds with anti-dengue properties [ 8 , 16 – 18 , 29 , 42 – 47 ], however, up to now there are no commercially available drugs for treatment of dengue.…”

“…Other compounds identified in T. officinale F9 were caffeic acid and caffeoylquinic acid derivatives. These molecules have been shown as inhibitors of some important viruses such as hepatitis B [ 62 ], influenza A [ 63 ], herpes simplex [ 64 ] and more recently, dengue virus [ 47 ]. In this last study, Zanello et al, show the effect of two derivatives on the four DENV serotypes.…”

A diarylamine derived from anthranilic acid inhibits ZIKV replication

“…Previous studies have shown that acid derivative-containing compounds have interfered in the replicative cycle of different virus families. Zanello and coworkers showed that N-sulfonyl anthranilic acid derivatives inhibited the replication of DENV by inactivating the RNA-dependent RNA polymerase, quinic acid derivatives inhibited the replication of DENV-3 assayed using a sub-genomic replicon in RepDV3-Huh 7.5 cells 39 . Additionally, anthranilic acid derivatives were reported to act as allosteric inhibitors by binding to HCV NS5B polymerase and inhibiting viral genome replication 40,41 .…”

Viral replicons as valuable tools for drug discovery

“…Interestingly, NS4b has no known enzymatic activity but is essential for replication, and is known to interact with viral and cellular proteins to form the dengue replication complex and subvert the cellular innate immune response [50]. Quinic acid derivatives were shown to reduce the amount of NS3 in treated DENV1 and DENV3 replicon-containing cells by FACS analysis [51]. Interestingly, genome replication and translation were excluded as the mode of action for some drug candidates, such as hirsutine, using the dengue subgenomic replicon system [52].…”